Inhibitors of spinster homolog 2 (spns2) for use in therapy

ABSTRACT

The present disclosure provides SPNS2 inhibitor compounds according to Formula (I) and their pharmaceutically acceptable salts, and/or tautomers as described in the disclosure, and the disclosure provides their pharmaceutical compositions and methods of use in therapy.

PRIORITY APPLICATION

This application claims priority to U.S. Patent Application Ser. No.63/076,111, filed Sep. 9, 2020, the disclosure of which is incorporatedherein in its entirety by reference.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

This invention was made with government support under R01GM121075 andR01AI144026 awarded by the National Institutes of Health. The governmenthas certain rights in the invention.

BACKGROUND

Sphingosine 1-phosphate (S1P) is a simple lipid that is chemotactic whenpresent extracellularly, but which is also a second messenger whenintracellular. These roles require compartmentalization, which isprovided in part by extrusion of S1P from cells. The S1P transporters,SPNS2 (endothelium) and MFSD2B (erythrocytes), release S1P from cells.When this release is coupled with S1P degradation in tissue parenchyma,a differential is generated between the extracellular (high) andintracellular (low) S1P concentrations. Mouse genetic studies indicatethat endothelial cells use SPNS2 to provide most of the S1P in lymph aswell as about one-third of plasma S1P, whereas erythrocytes provide theremainder of plasma S1P via MFSD2B. The S1P gradient in blood functionsboth to maintain endothelial barrier integrity and promote migration oflymphocytes from the thymus to the blood.

The lymph S1P gradient is particularly important for egress oflymphocytes from secondary lymphoid tissue into efferent lymph forcorrect temporal and spatial positioning of immune cells. However,on-target agonist activity at endothelial and cardiac S1P receptorsdrives adverse events such as first dose bradycardia.

SUMMARY

The present disclosure provides, in various embodiments, compounds andtheir pharmaceutically acceptable salts conforming to Formula I as SPNS2inhibitors that avoid on-target adverse activity:

X is a C₆-C₁₀-aryl or 5- to 10-membered heteroaryl (wherein 1 to 4heteroaryl ring members are independently selected from N, O, and S).

R¹ and R² are independently selected from the group consisting of H,C₁-C₆₋alkyl, C₁-C₆₋alkoxy, C₁₋₆₋haloalkoxy, C₃-C₈-cycloalkyl,C₁-C₆-haloalkyl, CN, halo, and —C(O)N(H)(C₁-C₆₋alkyl).

W is a bond, O, NH, —NHC(O)—, or —O—(N═)C(R)— (wherein R is H orC₁-C₆-alkyl).

V is selected from the group consisting of H, C₁-C₁₄-alkyl,C₂-C₁₂-alkenyl, (C₆-C₁₀)aryl, (C₆-C₁₀)heteroaryl,—C₁-C₁₀-alkyl-(C₆-C₁₀)aryl, —C₂-C₁₂-alkenyl-(C₆-C₁₀)aryl,—C₁-C₁₀-alkyl-(C₃-C₈)cycloalkyl, -(3- to 14-membered heterocycloalkyl)(wherein 1-4 heterocycloalkyl members are independently selected from N,O, and S), —(C₁-C₁₀)alkyl-(3- to 14-membered heterocycloalkyl) (wherein1-4 heterocycloalkyl members are independently selected from N, O, andS).

Y is selected from a bond, —NH—, (C₆-C₁₀)arylenyl, and(C₃-C₈)cycloalkylenyl.

Z is selected from a bond and —C(O)—.

R³ and R⁴ are independently selected from the group consisting of, H,C₁-C₆-alkyl, OH, C₁-C₆₋alkoxy, halo, —NRR′, —C(O)R, and —C(O)OR, whereinR and R′ are independently selected from H and C₁-C₆-alkyl.

R⁵ and R⁶ are independently selected from the group consisting of, H,C₁-C₆-alkyl, OH, C₁-C₆₋alkoxy, halo, —C(O)R, and —C(O)OR, wherein R is Hor C₁-C₆-alkyl, or R⁵ and R⁶, together with the carbon to which they arebound, form a —(C₃-C₈)cycloalkyl.

Subscript m is an integer selected from 0, 1, 2, 3, 4, 5, and 6.

Subscript n is an integer selected from 0, 1, and 2.

R⁷ and R⁸ are independently selected from the group consisting of H andC₁-C₆-alkyl, or R⁷ and R⁸, together with the nitrogen atom to which theyare bound, form a 5- to 7-membered heterocycloalkyl (wherein 1-4 otherheterocycloalkyl members are optionally independently selected from NH,0, and S).

Optionally, in some embodiments, one of R⁵ and R⁶ and one of R⁷ and R⁸,together with the carbon and nitrogen atoms to which they are bound,respectively, form a 4- to 7-membered heterocycloalkyl (wherein 1-4other heterocycloalkyl members are optionally independently selectedfrom NH, 0, and S).

Each alkyl, alkoxy, alkenyl, alkynyl, aryl, cycloalkyl,heterocycloalkyl, and heteroaryl is optionally substituted with 1-5substituents independently selected from the group consisting ofhydroxy, halo, C₁-C₆₋haloalkoxy, C₁-C₆-haloalkyl, —NR″₂,—NHC(O)(OC₁-C₆-alkyl), —NO₂, —CN, oxo, —C(O)OH, —C(O)O(C₁-C₆-alkyl),—C₁-C₆-alkyl(C₁-C₆-alkoxy), —C(O)NH₂, C₁-C₆-alkyl, —C(O)C₁-C₆-alkyl,—OC₁-C₆-alkyl, —Si(C₁-C₆-alkyl)₃, —S(O)₀₋₂—(C₁-C₆-alkyl), C₆-C₁₀-aryl,—(C₁-C₆-alkyl)(C₆-C₁₀-aryl), 3- to 14-membered heterocycloalkyl, and—(C₁-C₆-alkyl)-(3- to 14-membered heterocycle) (wherein 1-4 heterocyclemembers are independently selected from N, O, and S), and—O(C₆-C₁₄-aryl).

Each R″ is independently selected from the group consisting ofC₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₆-C₁₀-aryl, 3- to14-membered heterocycloalkyl and —(C₁-C₆-alkyl)-(3- to 14-memberedheterocycloalkyl) (wherein 1-4 ring members are independently selectedfrom N, O, and S), and 5- to 10-membered heteroaryl (wherein 1-4heteroaryl members are independently selected from N, O, and S.

Another embodiment of the disclosure is a pharmaceutical compositioncomprising a compound of Formula I or a pharmaceutically acceptable saltthereof.

The disclosure also provides, in an embodiment, a method of inhibitingspinster homolog 2 (SPNS2), comprising contacting SPNS2 with aneffective amount of a compound of Formula I or a pharmaceuticallyacceptable salt thereof.

Still another embodiment is a method of treating a patient afflicted bya neoplastic disease, comprising administering to the patient atherapeutically effective amount of a compound of Formula I or apharmaceutically acceptable salt thereof.

In an embodiment, the disclosure provides a method of treating a patientafflicted with an allergic disease, comprising administering to thepatient a therapeutically effective amount of a compound of Formula I ora pharmaceutically acceptable salt thereof.

In another embodiment, the disclosure provides a method of treating apatient afflicted with an autoimmune disease, comprising administeringto the patient a therapeutically effective amount of a compound ofFormula I or a pharmaceutically acceptable salt thereof.

DETAILED DESCRIPTION

In a properly functioning immune system, the proper cells get to theproper places at the proper times. Gradients of the chemotactic lipid,sphingosine 1-phosphate (S1P), enable correct positioning of immunecells; lymphocyte egress from secondary lymphoid tissues is particularlydependent on S1P signaling. S1P's role in lymphocyte trafficking wasdiscovered when the mechanism of action of the immunosuppressive drugfingolimod (FTY720) was investigated. Fingolimod's active metabolite,phospho-FTY720, desensitizes lymphocyte S1P1 receptors; thereby,rendering these cells unable to detect the S1P-rich environment ofefferent lymph¹. The resulting lymphopenia is now recognized as ageneral property of S1P1 receptor agonists. Although fingolimodeventually became a medicine for treating relapsing remitting multiplesclerosis², S1P1 receptor agonists have several on target liabilitiesincluding initial dose bradycardia and compromised endothelial barrierfunction². Therefore, alternative strategies to achieveimmunosuppression by modulating S1P signaling without undesirableon-target activity are needed.

S1P is synthesized ubiquitously, but its intracellular accumulation islimited by degradation and export. In lymph nodes (LN), brisk catabolicactivity by S1P lyase keeps S1P³ low while lymph endothelial cellsextrude S1P into lymph via a transporter, SPNS2⁴, resulting in alymph-LN S1P gradient. Vascular (blood) S1P gradients are likewisemaintained by prominent S1P catabolic activity in tissue parenchymacoupled with the extrusion of S1P into plasma. About ⅓ of plasma S1P isprovided by vascular endothelial cells via SPNS2⁴, with the remainderbeing released from red blood cells (RBCs) by a different S1Ptransporter. The transporter was subsequently discovered to be MFSD2B,which is an erythroid lineage-specific major facilitator superfamilymember that is distantly related to SPNS2⁵′6. Germ line deletion ofMfsd2b results in a 50% decrease in plasma S1P but an astonishing60-fold increase in RBC S1P; however, these animals are notlymphopenic⁵. RBCs lack S1P catabolic enzymes but express sphingosinekinase type 1 (SphK1), which accounts for the high levels of S1P inwhole blood. Blood S1P gradients are necessary to maintain endothelialbarrier integrity⁷. Indeed, Ma has proposed that vascular S1P gradientsare a fundamental property of the closed circulatory systems ofvertebrates⁹.

The role of the catabolic enzyme S1P lyase in maintaining low LN S1Ppredicts that S1P lyase inhibitors will eliminate the gradient, whichwill modulate the immune system by disrupting lymphocyte traffickinganalogous to S1P1 agonists. Indeed, S1P lyase deficiency, whetheraccomplished through genetic manipulation of mice or S1P lyase inhibitoradministration, raises S1P levels in tissues, including lymph nodes,with a resulting lymphopenia^(3,10). However, administering a selectiveS1P lyase inhibitor to rats and inducing global deletion of the gene(Sgpl1) in mice were both found to be nephrotoxic¹⁰. Furthermore, humansdeficient in S1P lyase activity because of SGPL1 variant alleles exhibitmultiple pathologies including steroid resistant nephrosis, adrenalinsufficiency, and ichthyosis^(11,12). Such observations appear toeliminate S1P lyase as a therapeutic target.

Mice rendered deficient in Spns2 either through germ line orendothelium-specific deletion of Spns2, have a 10-fold decrease in S1Plevels in thoracic duct lymph and are lymphopenic but the vascular S1Pgradient is less affected (30% reduction in plasma S1P)⁴. These resultsvalidate the data disclosed herein that SPNS2 inhibitors of thisdisclosure, by preventing the formation of the lymph S1P gradient,recapitulate the therapeutic efficacy of S1P1 receptor agonists withouttheir adverse events.

Application of an SPNS2 inhibitor in immuno-oncology comes from anothermouse genetics study. In a screen of 810 mouse strains with differentgerm line gene deletions, Spns2⁴ mice were found to have remarkably lowmetastatic colonization of the lungs when injected with B16-F10 melanomacells¹³. This effect was observed with other lung metastaticcolonization models and in similar models in liver. As expected, thetotal number of immune cells in the lung was reduced in the lymphopenicSpns2^(−/−) mice, but the lung resident population was proportionallyenriched in natural killer and CD8⁺ effector cells¹³.

Thus, results from the study of mice rendered deficient in Spns2indicate that SPNS2 inhibitors are immunomodulatory. The SPNS2inhibitors of the disclosure recapitulate the SPNS2 null phenotype, andthey and enable S1P transport inhibition as a viable therapeuticstrategy as well as providing heretofore unavailable chemical biologytools to explore S1P physiology in vivo.

Definitions

“Alkyl” refers to straight or branched chain hydrocarbyl including from1 to about 20 carbon atoms. For instance, an alkyl can have from 1 to 10carbon atoms or 1 to 6 carbon atoms. Exemplary alkyl includes straightchain alkyl groups such as methyl, ethyl, propyl, butyl, pentyl, hexyl,heptyl, octyl, nonyl, decyl, undecyl, dodecyl, and the like, and alsoincludes branched chain isomers of straight chain alkyl groups, forexample without limitation, —CH(CH₃)₂, —CH(CH₃)(CH₂CH₃), —CH(CH₂CH₃)₂,—C(CH₃)₃, —C(CH₂CH₃)₃, —CH₂CH(CH₃)₂, —CH₂CH(CH₃)(CH₂CH₃),—CH₂CH(CH₂CH₃)₂, —CH₂ C(CH₃)₃, —CH₂C(CH₂CH₃)₃, —CH(CH₃)CH(CH₃)(CH₂CH₃),—CH₂CH₂CH(CH₃)₂, —CH₂CH₂C H(CH₃)(CH₂CH₃), —CH₂CH₂CH(CH₂CH₃)₂,—CH₂CH₂C(CH₃)₃, —CH₂CH₂C(CH₂CH₃)₃, —CH(CH₃)CH₂CH(CH₃)₂,—CH(CH₃)CH(CH₃)CH(CH₃)₂, and the like. Thus, alkyl groups includeprimary alkyl groups, secondary alkyl groups, and tertiary alkyl groups.An alkyl group can be unsubstituted or optionally substituted with oneor more substituents as described herein below.

The phrase “substituted alkyl” refers to alkyl substituted at one ormore positions, for example, 1, 2, 3, 4, 5, or even 6 positions, whichsubstituents are attached at any available atom to produce a stablecompound, with substitution as described herein. “Optionally substitutedalkyl” refers to alkyl or substituted alkyl.

A “haloalkyl” is an alkyl, as defined herein, that is substituted withat least one, such as 1-8, halo substituents.

Each of the terms “halogen,” “halide,” and “halo” refers to —F, —Cl,—Br, or —I.

The term “alkenyl” refers to straight or branched chain hydrocarbylgroups including from 2 to about 20 carbon atoms having 1-3, 1-2, or atleast one carbon to carbon double bond. An alkenyl group can beunsubstituted or optionally substituted with one or more substituents asdescribed herein below.

“Substituted alkenyl” refers to alkenyl substituted at 1 or more, e.g.,1, 2, 3, 4, 5, or even 6 positions, which substituents are attached atany available atom to produce a stable compound, with substitution asdescribed herein. “Optionally substituted alkenyl” refers to alkenyl orsubstituted alkenyl.

“Alkyne or “alkynyl” refers to a straight or branched chain unsaturatedhydrocarbon having the indicated number of carbon atoms and at least onetriple bond. Examples of a (C₂-C₈)alkynyl group include, but are notlimited to, acetylene, propyne, 1-butyne, 2-butyne, 1-pentyne,2-pentyne, 1-hexyne, 2-hexyne, 3-hexyne, 1-heptyne, 2-heptyne,3-heptyne, 1-octyne, 2-octyne, 3-octyne and 4-octyne. An alkynyl groupcan be unsubstituted or optionally substituted with one or moresubstituents as described herein below.

“Substituted alkynyl” refers to an alkynyl substituted at 1 or more,e.g., 1, 2, 3, 4, 5, or even 6 positions, which substituents areattached at any available atom to produce a stable compound, withsubstitution as described herein. “Optionally substituted alkynyl”refers to alkynyl or substituted alkynyl.

The term “alkoxy” refers to an —O-alkyl group having the indicatednumber of carbon atoms. For example, a (C₁-C₆)alkoxy group includes—O-methyl, —O-ethyl, —O-propyl, —O— isopropyl, —O-butyl, —O-sec-butyl,—O-tert-butyl, —O-pentyl, —O-isopentyl, —O-neopentyl, —O— hexyl,—O-isohexyl, and —O-neohexyl.

A “haloalkoxy” is an alkoxy, as defined herein, that is substituted withat least one, such as 1-8, halo substituents.

The term “cycloalkyl” refers to a monocyclic, bicyclic, tricyclic, orpolycyclic, 3- to 14-membered ring system, which is either saturated,such as “cycloalkyl,” or unsaturated, such as “cycloalkenyl.” The term“cycloalkenyl” refers specifically to cyclic alkenyl, such asC₃-C₆-cycloalkenyl. The cycloalkyl may be attached via any atom.Cycloalkyl, for instance, also contemplates fused rings wherein, forinstance, a cycloalkyl is fused to an aryl or heteroaryl ring as definedherein. Representative examples of cycloalkyl include, but are notlimited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cyclopropenyl, cyclobutenyl, cyclopentenyl, and cyclohexenyl. Acycloalkyl group can be unsubstituted or optionally substituted with oneor more substituents as described herein.

“Substituted cycloalkyl” refers to cycloalkyl substituted at 1 or more,e.g., 1, 2, 3, 4, 5, or even 6 positions, which substituents areattached at any available atom to produce a stable compound, withsubstitution as described herein. “Optionally substituted cycloalkyl”refers to cycloalkyl or substituted cycloalkyl.

“Aryl” when used alone or as part of another term means a carbocyclicaromatic group whether or not fused having the number of carbon atomsdesignated or if no number is designated, up to 14 carbon atoms, such asa C₆-C₁₄-aryl. Particular aryl groups are phenyl, naphthyl, biphenyl,phenanthrenyl, naphthacenyl, and the like (see e.g. Lang's Handbook ofChemistry (Dean, J. A., ed) 13^(th) ed. Table 7-2 [1985]). A particulararyl is phenyl. “Aryl” also includes aromatic ring systems that areoptionally fused with a cycloalkyl ring, as herein defined. An arylgroup can be unsubstituted or optionally substituted with one or moresubstituents as described herein below.

A “substituted aryl” is an aryl that is independently substituted withone or more substituents attached at any available atom to produce astable compound, wherein the substituents are as described herein.“Optionally substituted aryl” refers to aryl or substituted aryl.

The term “heteroatom” refers to N, O, and S. Disclosed compounds thatcontain N or S atoms can be optionally oxidized to the correspondingN-oxide, sulfoxide, or sulfone compounds.

“Heteroaryl,” alone or in combination with any other moiety describedherein, refers to a monocyclic aromatic ring structure containing 5 to10, such as 5 or 6 ring atoms, or a bicyclic aromatic group having 8 to10 atoms, containing one or more, such as 1-4, 1-3, or 1-2, heteroatomsindependently selected from the group consisting of O, S, and N.Heteroaryl is also intended to include oxidized S or N, such assulfinyl, sulfonyl and N-oxide of a tertiary ring nitrogen. A carbon orheteroatom is the point of attachment of the heteroaryl ring structuresuch that a stable compound is produced. Examples of heteroaryl groupsinclude, but are not limited to, pyridinyl, pyridazinyl, pyrazinyl,quinaoxalyl, indolizinyl, benzo[b]thienyl, quinazolinyl, purinyl,indolyl, quinolinyl, pyrimidinyl, pyrrolyl, pyrazolyl, oxazolyl,thiazolyl, thienyl, isoxazolyl, oxathiadiazolyl, isothiazolyl,tetrazolyl, imidazolyl, triazolyl, furanyl, benzofuryl, and indolyl. Aheteroaryl group can be unsubstituted or optionally substituted with oneor more substituents as described herein below.

A “substituted heteroaryl” is a heteroaryl that is independentlysubstituted, unless indicated otherwise, with one or more, e.g., 1, 2,3, 4 or 5, also 1, 2, or 3 substituents, also 1 substituent, attached atany available atom to produce a stable compound, wherein thesubstituents are as described herein. “Optionally substitutedheteroaryl” refers to heteroaryl or substituted heteroaryl.

“Heterocycloalkyl” means a saturated or unsaturated non-aromaticmonocyclic, bicyclic, tricyclic or polycyclic ring system that has from3 to 14, such as 3 to 6, atoms in which from 1 to 3 carbon atoms in thering are replaced by heteroatoms of O, S or N. A heterocycloalkyl isoptionally fused with aryl or heteroaryl of 5-6 ring members, andincludes oxidized S or N, such as sulfinyl, sulfonyl and N-oxide of atertiary ring nitrogen. The point of attachment of the heterocycloalkylring is at a carbon or heteroatom such that a stable ring is retained.Examples of heterocycloalkyl groups include without limitationmorpholino, tetrahydrofuranyl, dihydropyridinyl, piperidinyl,pyrrolidinyl, piperazinyl, dihydrobenzofuryl, and dihydroindolyl. Ahetercycloalkyl group can be unsubstituted or optionally substitutedwith one or more substituents as described herein below.

“Optionally substituted heterocycloalkyl” denotes a heterocycloalkylthat is substituted with 1 to 3 substituents, e.g., 1, 2 or 3substituents, attached at any available atom to produce a stablecompound, wherein the substituents are as described herein.

The term “nitrile” or “cyano” can be used interchangeably and refer to a—CN group which is bound to a carbon atom of a heteroaryl ring, arylring and a heterocycloalkyl ring.

The term “oxo” refers to a ═O atom attached to a saturated orunsaturated moiety. The ═O atom can be attached to a carbon, sulfur, ornitrogen atom that is part of a cyclic or acyclic moiety.

A “hydroxyl” or “hydroxy” refers to an —OH group.

The substituent —CO₂H may be replaced with bioisosteric replacementssuch as:

and the like, wherein R has the same definition as R^(A) as definedherein. See, e.g., THE PRACTICE OF MEDICINAL CHEMISTRY (Academic Press:New York, 1996), at page 203.

Compounds described herein can exist in various isomeric forms,including configurational, geometric, and conformational isomers,including, for example, cis- or trans-conformations. The compounds mayalso exist in one or more tautomeric forms, including both singletautomers and mixtures of tautomers. The term “isomer” is intended toencompass all isomeric forms of a compound of this disclosure, includingtautomeric forms of the compound. The compounds of the presentdisclosure may also exist in open-chain or cyclized forms. In some casesone or more of the cyclized forms may result from the loss of water. Thespecific composition of the open-chain and cyclized forms may bedependent on how the compound is isolated, stored or administered. Forexample, the compound may exist primarily in an open-chained form underacidic conditions but cyclize under neutral conditions. All forms areincluded in the disclosure.

Some compounds described herein can have asymmetric centers andtherefore exist in different enantiomeric and diastereomeric forms. Acompound as described herein can be in the form of an optical isomer ora diastereomer. Accordingly, the disclosure encompasses compounds andtheir uses as described herein in the form of their optical isomers,diastereoisomers and mixtures thereof, including a racemic mixture.Optical isomers of the compounds of the disclosure can be obtained byknown techniques such as asymmetric synthesis, chiral chromatography,simulated moving bed technology or via chemical separation ofstereoisomers through the employment of optically active resolvingagents.

Unless otherwise indicated, the term “stereoisomer” means onestereoisomer of a compound that is substantially free of otherstereoisomers of that compound. Thus, a stereomerically pure compoundhaving one chiral center will be substantially free of the oppositeenantiomer of the compound. A stereomerically pure compound having twochiral centers will be substantially free of other diastereomers of thecompound. A typical stereomerically pure compound comprises greater thanabout 80% by weight of one stereoisomer of the compound and less thanabout 20% by weight of other stereoisomers of the compound, for examplegreater than about 90% by weight of one stereoisomer of the compound andless than about 10% by weight of the other stereoisomers of thecompound, or greater than about 95% by weight of one stereoisomer of thecompound and less than about 5% by weight of the other stereoisomers ofthe compound, or greater than about 97% by weight of one stereoisomer ofthe compound and less than about 3% by weight of the other stereoisomersof the compound, or greater than about 99% by weight of one stereoisomerof the compound and less than about 1% by weight of the otherstereoisomers of the compound. The stereoisomer as described above canbe viewed as composition comprising two stereoisomers that are presentin their respective weight percentages described herein.

If there is a discrepancy between a depicted structure and a name givento that structure, then the depicted structure controls. Additionally,if the stereochemistry of a structure or a portion of a structure is notindicated with, for example, bold or dashed lines, the structure orportion of the structure is to be interpreted as encompassing allstereoisomers of it. In some cases, however, where more than one chiralcenter exists, the structures and names may be represented as singleenantiomers to help describe the relative stereochemistry. Those skilledin the art of organic synthesis will know if the compounds are preparedas single enantiomers from the methods used to prepare them.

As used herein, and unless otherwise specified to the contrary, the term“compound” is inclusive in that it encompasses a compound or apharmaceutically acceptable salt, stereoisomer, and/or tautomer thereof.Thus, for instance, a compound of Formula I includes a pharmaceuticallyacceptable salt of the compound.

In this description, a “pharmaceutically acceptable salt” is apharmaceutically acceptable, organic or inorganic acid or base salt of acompound described herein. Representative pharmaceutically acceptablesalts include, e.g., alkali metal salts, alkali earth salts, ammoniumsalts, water-soluble and water-insoluble salts, such as the acetate,amsonate (4,4-diaminostilbene-2, 2-disulfonate), benzenesulfonate,benzonate, bicarbonate, bisulfate, bitartrate, borate, bromide,butyrate, calcium, calcium edetate, camsylate, carbonate, chloride,citrate, clavulariate, dihydrochloride, edetate, edisylate, estolate,esylate, fiunarate, gluceptate, gluconate, glutamate,glycollylarsanilate, hexafluorophosphate, hexylresorcinate, hydrabamine,hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate,lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate,methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate,N-methylglucamine ammonium salt, 3-hydroxy-2-naphthoate, oleate,oxalate, palmitate, pamoate (1,1-methene-bis-2-hydroxy-3-naphthoate,einbonate), pantothenate, phosphate/diphosphate, picrate,polygalacturonate, propionate, p-toluenesulfonate, salicylate, stearate,subacetate, succinate, sulfate, sulfosaliculate, suramate, tannate,tartrate, teoclate, tosylate, triethiodide, and valerate salts. Apharmaceutically acceptable salt can have more than one charged atom inits structure. In this instance the pharmaceutically acceptable salt canhave multiple counterions. Thus, a pharmaceutically acceptable salt canhave one or more charged atoms and/or one or more counterions.

The terms “treat”, “treating” and “treatment” refer to the ameliorationor eradication of a disease or symptoms associated with a disease. Incertain embodiments, such terms refer to minimizing the spread orworsening of the disease resulting from the administration of one ormore prophylactic or therapeutic agents to a patient with such adisease.

The terms “prevent,” “preventing,” and “prevention” refer to theprevention of the onset, recurrence, or spread of the disease in apatient resulting from the administration of a prophylactic ortherapeutic agent.

The term “effective amount” refers to an amount of a compound asdescribed herein or other active ingredient sufficient to provide atherapeutic or prophylactic benefit in the treatment or prevention of adisease or to delay or minimize symptoms associated with a disease.Further, a therapeutically effective amount with respect to a compoundas described herein means that amount of therapeutic agent alone, or incombination with other therapies, that provides a therapeutic benefit inthe treatment or prevention of a disease. Used in connection with acompound as described herein, the term can encompass an amount thatimproves overall therapy, reduces or avoids symptoms or causes ofdisease, or enhances the therapeutic efficacy of or synergies withanother therapeutic agent.

A “patient” or subject” includes an animal, such as a human, cow, horse,sheep, lamb, pig, chicken, turkey, quail, cat, dog, mouse, rat, rabbitor guinea pig. In accordance with some embodiments, the animal is amammal such as a non-primate and a primate (e.g., monkey and human). Inone embodiment, a patient is a human, such as a human infant, child,adolescent or adult.

“Inhibitor” means a compound that induces dose dependent lymphopenia anda modest decrease in plasma S1P. In an embodiment, an inhibitor binds toSPNS2.

Compounds

As described generally above, the present disclosure provides compounds,pharmaceutically acceptable salts, and/or tautomers thereof, wherein thecompounds conform to Formula I:

X is a C₆-C₁₀-aryl or 5- to 10-membered heteroaryl (wherein 1 to 4heteroaryl ring members are independently selected from N, O, and S).

R¹ and R² are independently selected from the group consisting of H,C₁-C₆₋alkyl, C₁-C₆₋alkoxy, C₁₋₆₋haloalkoxy, C₃-C₈-cycloalkyl,C₁-C₆-haloalkyl, CN, halo, and —C(O)N(H)(C₁-C₆₋alkyl).

W is a bond, O, NH, —NHC(O)—, or —O—(N═)C(R)— (wherein R is H orC₁-C₆-alkyl).

V is selected from the group consisting of H, C₁-C₁₄-alkyl,C₂-C₁₂-alkenyl, (C₆-C₁₀)aryl, (C₆-C₁₀)heteroaryl,—C₁-C₁₀-alkyl-(C₆-C₁₀)aryl, —C₂-C₁₂-alkenyl-(C₆-C₁₀)aryl,—C₁-C₁₀-alkyl-(C₃-C₈)cycloalkyl, -(3- to 14-membered heterocycloalkyl)(wherein 1-4 heterocycloalkyl members are independently selected from N,O, and S), —(C₁-C₁₀)alkyl-(3- to 14-membered heterocycloalkyl) (wherein1-4 heterocycloalkyl members are independently selected from N, O, andS).

Y is selected from a bond, —NH—, (C₆-C₁₀)arylenyl, and(C₃-C₈)cycloalkylenyl.

Z is selected from a bond and —C(O)—.

R³ and R⁴ are independently selected from the group consisting of, H,C₁-C₆-alkyl, OH, C₁-C₆₋alkoxy, halo, —NRR′, —C(O)R, and —C(O)OR, whereinR and R′ are independently selected from H and C₁-C₆-alkyl.

R⁵ and R⁶ are independently selected from the group consisting of, H,C₁-C₆-alkyl, OH, C₁-C₆₋alkoxy, halo, —C(O)R, and —C(O)OR, wherein R is Hor C₁-C₆-alkyl, or R⁵ and R⁶, together with the carbon to which they arebound, form a —(C₃-C₈)cycloalkyl.

Subscript m is an integer selected from 0, 1, 2, 3, 4, 5, and 6.

Subscript n is an integer selected from 0, 1, and 2.

R⁷ and R⁸ are independently selected from the group consisting of H andC₁-C₆-alkyl, or R⁷ and R⁸, together with the nitrogen atom to which theyare bound, form a 5- to 7-membered heterocycloalkyl (wherein 1-4 otherheterocycloalkyl members are optionally independently selected from NH,O, and S).

Optionally, in some embodiments, one of R⁵ and R⁶ and one of R⁷ and R⁸,together with the carbon and nitrogen atoms to which they are bound,respectively, form a 4- to 7-membered heterocycloalkyl (wherein 1-4other heterocycloalkyl members are optionally independently selectedfrom NH, O, and S). In additional embodiments, the heterocycloalkyl is a5- to 7-membered heterocycloalkyl.

Each alkyl, alkoxy, alkenyl, alkynyl, aryl, cycloalkyl,heterocycloalkyl, and heteroaryl is optionally substituted with 1-5substituents independently selected from the group consisting ofhydroxy, halo, C₁-C₆₋haloalkoxy, C₁-C₆-haloalkyl, —NR″₂,—NHC(O)(OC₁-C₆-alkyl), —NO₂, —CN, oxo, —C(O)OH, —C(O)O(C₁-C₆-alkyl),—C₁-C₆-alkyl(C₁-C₆-alkoxy), —C(O)NH₂, C₁-C₆-alkyl, —C(O)C₁-C₆-alkyl,—OC₁-C₆-alkyl, —Si(C₁-C₆-alkyl)₃, —S(O)₀₋₂—(C₁-C₆-alkyl), C₆-C₁₀-aryl,—(C₁-C₆-alkyl)(C₆-C₁₀-aryl), 3- to 14-membered heterocycloalkyl, and—(C₁-C₆-alkyl)-(3- to 14-membered heterocycle) (wherein 1-4 heterocyclemembers are independently selected from N, O, and S), and—O(C₆-C₁₄-aryl).

Each R″ is independently selected from the group consisting ofC₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₆-C₁₀-aryl, 3- to14-membered heterocycloalkyl and —(C₁-C₆-alkyl)-(3- to 14-memberedheterocycloalkyl) (wherein 1-4 ring members are independently selectedfrom N, O, and S), and 5- to 10-membered heteroaryl (wherein 1-4heteroaryl members are independently selected from N, O, and S.

In some embodiments, X is phenyl.

In various embodiments, optionally in combination with any otherembodiment herein described, each of R¹ and R² is H.

In still further embodiments, optionally in combination with any otherembodiment herein described, each of Y and Z is a bond.

In some embodiments, optionally in combination with any other embodimentherein described, m is selected from 0, 1, 2, 3, and 4. For example, mis 1, 2, or 3. In illustrative embodiments, m is 3 and n is 1 or 2.

In other embodiments, optionally in combination with any otherembodiment herein described, R⁷ and R⁸ are independently selected fromthe group consisting of H and C₁-C₆-alkyl. For example, in someembodiments, each of R⁷ and R⁸ is H.

In various embodiments, optionally in combination with any otherembodiment herein described, Y is (C₃-C₈)cycloalkylenyl and Z is a bond.Various combinations are contemplated in this context: in an embodiment,m is 0 or 1. In another embodiment, m is 0. In still another embodiment,optionally in combination with other embodiments described herein, n is0.

In additional embodiments, optionally in combination with any otherembodiment herein described, Y is —NH—. Further, optionally incombination with this embodiment, Z is —C(O)—. Variations of theseembodiments reside in the provision of m as 0 or 1.

In still further embodiments, optionally in combination with any otherembodiment herein described, one of R⁵ and R⁶ and one of R⁷ and R⁸,together with the carbon and nitrogen atoms to which they are bound,respectively, form a 5- to 7-membered heterocycloalkyl. In anembodiment, the other one of R⁷ and R⁸ is H.

The present disclosure provides specific examples of Formula Icompounds, and their pharmaceutically acceptable salts, and/or tautomersthereof as set forth in Table 1 below.

TABLE 1 Examples of Formula I Compounds Compound Structure 5a

5b

5c

5d

5e

5f

5g

5h

5i

5j

5k

5l

5m

5n

5n

5p

5q

5r

5s

5t

5u

5v

5w

5x

5y

6a

6b

6c

6d

6e

6f

7a

7b

9a

9b

9c

9d

9e

9f

9g

9h

9i

9j

9k

9l

9m

9n

9o

9p

9q

9r

9s

9t

9u

9v

9w

9x

9y

9z

 9aa

 9ab

 9ac

 9ad

 9ae

 9af

 9ag

 9ah

 9ai

 9aj

 9ak

 9al

13a 

13b 

13c 

13d 

16a 

16b 

19a 

19b 

19c 

19d 

21 

28 

Pharmaceutical Composition

The disclosure also provides a pharmaceutical composition comprising atherapeutically effective amount of one or more compounds according toFormula I or a pharmaceutically acceptable salt, stereoisomer, and/ortautomer thereof in admixture with a pharmaceutically acceptablecarrier. In some embodiments, the composition further contains, inaccordance with accepted practices of pharmaceutical compounding, one ormore additional therapeutic agents, pharmaceutically acceptableexcipients, diluents, adjuvants, stabilizers, emulsifiers,preservatives, colorants, buffers, flavor imparting agents.

In one embodiment, the pharmaceutical composition comprises a compoundselected from those illustrated in Table 1 or a pharmaceuticallyacceptable salt, stereoisomer, and/or tautomer thereof, and apharmaceutically acceptable carrier.

The pharmaceutical composition of the present disclosure is formulated,dosed, and administered in a fashion consistent with good medicalpractice. Factors for consideration in this context include theparticular disorder being treated, the particular subject being treated,the clinical condition of the subject, the cause of the disorder, thesite of delivery of the agent, the method of administration, thescheduling of administration, and other factors known to medicalpractitioners.

The “therapeutically effective amount” of a compound (or apharmaceutically acceptable salt, stereoisomer, and/or tautomer thereofthat is administered is governed by such considerations, and is theminimum amount necessary to induce dose dependent lymphopenia and amodest decrease in plasma S1P, or to inhibit SPNS2 activity, or both.Such amount may be below the amount that is toxic to normal cells, orthe subject as a whole. Generally, the initial therapeutically effectiveamount of a compound (or a pharmaceutically acceptable salt,stereoisomer, or tautomer thereof) of the present disclosure that isadministered is in the range of about 0.01 to about 200 mg/kg or about0.1 to about 20 mg/kg of patient body weight per day, with the typicalinitial range being about 0.3 to about 15 mg/kg/day. Oral unit dosageforms, such as tablets and capsules, may contain from about 1 mg toabout 1000 mg of a compound (or a pharmaceutically acceptable salt,stereoisomer, or tautomer thereof) of the present disclosure. In anotherembodiment, such dosage forms contain from about 50 mg to about 500 mgof a compound (or a pharmaceutically acceptable salt, stereoisomer, ortautomer thereof) of the present disclosure. In yet another embodiment,such dosage forms contain from about 25 mg to about 200 mg of a compound(or a pharmaceutically acceptable salt, stereoisomer, or tautomerthereof) of the present disclosure. In still another embodiment, suchdosage forms contain from about 10 mg to about 100 mg of a compound (ora pharmaceutically acceptable salt, stereoisomer, or tautomer thereof)of the present disclosure. In a further embodiment such dosage formscontain from about 5 mg to about 50 mg of a compound (or apharmaceutically acceptable salt, stereoisomer, or tautomer thereof) ofthe present disclosure.

The disclosed compositions can be administered orally, topically,parenterally, by inhalation or spray or rectally in dosage unitformulations. The term parenteral as used herein includes subcutaneousinjections, intravenous, intramuscular, intrasternal injection orinfusion techniques.

Suitable oral compositions as described herein include withoutlimitation tablets, troches, lozenges, aqueous or oily suspensions,dispersible powders or granules, emulsion, hard or soft capsules,syrups, or elixirs.

Also encompassed by the present disclosure are pharmaceuticalcompositions suitable for single unit dosages that comprise a compoundof the disclosure or its pharmaceutically acceptable stereoisomer, salt,or tautomer and a pharmaceutically acceptable carrier.

Compositions suitable for oral use may be prepared according to anymethod known to the art for the manufacture of pharmaceuticalcompositions. For instance, liquid formulations of the inventivecompounds contain one or more agents selected from the group consistingof sweetening agents, flavoring agents, coloring agents and preservingagents in order to provide pharmaceutically palatable preparations ofthe SPNS2 inhibitor.

For tablet compositions, a compound of the present disclosure inadmixture with non-toxic pharmaceutically acceptable excipients is usedfor the manufacture of tablets. Examples of such excipients includewithout limitation inert diluents, such as calcium carbonate, sodiumcarbonate, lactose, calcium phosphate or sodium phosphate; granulatingand disintegrating agents, for example, corn starch, or alginic acid;binding agents, for example starch, gelatin or acacia, and lubricatingagents, for example magnesium stearate, stearic acid or talc. Thetablets may be uncoated or they may be coated by known coatingtechniques to delay disintegration and absorption in thegastrointestinal tract and thereby to provide a sustained therapeuticaction over a desired time period. For example, a time delay materialsuch as glyceryl monostearate or glyceryl distearate may be employed.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with water or anoil medium, for example peanut oil, liquid paraffin or olive oil.

For aqueous suspensions, a compound of the present disclosure is admixedwith excipients suitable for maintaining a stable suspension. Examplesof such excipients include without limitation are sodiumcarboxymethylcellulose, methylcellulose, hydropropylmethylcellulose,sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia.

Oral suspensions can also contain dispersing or wetting agents, such asnaturally-occurring phosphatide, for example, lecithin, or condensationproducts of an alkylene oxide with fatty acids, for examplepolyoxyethylene stearate, or condensation products of ethylene oxidewith long chain aliphatic alcohols, for example,heptadecaethyleneoxycetanol, or condensation products of ethylene oxidewith partial esters derived from fatty acids and a hexitol such aspolyoxyethylene sorbitol monooleate, or condensation products ofethylene oxide with partial esters derived from fatty acids and hexitolanhydrides, for example polyethylene sorbitan monooleate. The aqueoussuspensions may also contain one or more preservatives, for exampleethyl, or n-propyl p-hydroxybenzoate, one or more coloring agents, oneor more flavoring agents, and one or more sweetening agents, such assucrose or saccharin.

Oily suspensions may be formulated by suspending a compound of thepresent disclosure in a vegetable oil, for example arachis oil, oliveoil, sesame oil or coconut oil, or in a mineral oil such as liquidparaffin. The oily suspensions may contain a thickening agent, forexample beeswax, hard paraffin or cetyl alcohol.

Sweetening agents such as those set forth above, and flavoring agentsmay be added to provide palatable oral preparations. These compositionsmay be preserved by the addition of an anti-oxidant such as ascorbicacid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide a compound of the presentdisclosure in admixture with a dispersing or wetting agent, suspendingagent and one or more preservatives. Suitable dispersing or wettingagents and suspending agents are exemplified by those already mentionedabove. Additional excipients, for example sweetening, flavoring andcoloring agents, may also be present.

Pharmaceutical compositions of the present disclosure may also be in theform of oil-in-water emulsions. The oily phase may be a vegetable oil,for example olive oil or arachis oil, or a mineral oil, for exampleliquid paraffin or mixtures of these. Suitable emulsifying agents may benaturally-occurring gums, for example gum acacia or gum tragacanth,naturally-occurring phosphatides, for example soy bean, lecithin, andesters or partial esters derived from fatty acids and hexitol,anhydrides, for example sorbitan monoleate, and condensation reactionproducts of the said partial esters with ethylene oxide, for examplepolyoxyethylene sorbitan monoleate. The emulsions may also containsweetening and flavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitol or sucrose. Such formulations mayalso contain a demulcent, a preservative, and flavoring and coloringagents. The pharmaceutical compositions may be in the form of a sterileinjectable, an aqueous suspension or an oleaginous suspension. Thissuspension may be formulated according to the known art using thosesuitable dispersing or wetting agents and suspending agents which havebeen mentioned above. The sterile injectable preparation may also besterile injectable solution or suspension in a non-toxic parentallyacceptable diluent or solvent, for example as a solution in1,3-butanediol. Among the acceptable vehicles and solvents that may beemployed are water, Ringer's solution and isotonic sodium chloridesolution. In addition, sterile, fixed oils are conventionally employedas a solvent or suspending medium. For this purpose any bland fixed oilmay be employed including synthetic mono- or diglycerides. In addition,fatty acids such as oleic acid find use in the preparation ofinjectables.

The compounds of Formula I may also be administered in the form ofsuppositories for rectal administration of the drug. These compositionscan be prepared by mixing the drug with a suitable non-irritatingexcipient which is solid at ordinary temperatures but liquid at therectal temperature and will therefore melt in the rectum to release thedrug. Such materials are cocoa butter and polyethylene glycols.

Compositions for parenteral administrations are administered in asterile medium. Depending on the vehicle used and concentration theconcentration of the drug in the formulation, the parenteral formulationcan either be a suspension or a solution containing dissolved drug.Adjuvants such as local anesthetics, preservatives and buffering agentscan also be added to parenteral compositions.

Methods of Use

S1P gradients are chemotactic, a property that enables correctpositioning of immune cells, and they help to maintain endothelialbarrier integrity. Accordingly, S1P gradients are manipulated fortherapeutic benefit using Formula I compounds because they target theendothelial S1P exporter, SPNS2.

Thus, in one embodiment, the disclosure provides a method of inhibitingspinster homolog 2 (SPNS2). The method comprises contacting SPNS2 withan effective amount of a compound as described herein. In someembodiments, the contacting occurs in vitro. In other embodiments, thecontacting occurs ex vivo or in vivo.

Another embodiment is a method of treating a patient afflicted by aneoplastic disease, comprising administering to the patient atherapeutically effective amount a compound as described herein. In someembodiments, the neoplastic disease is metastatic neoplasms.

An additional embodiment is a method of treating a patient afflictedwith an allergic disease, comprising administering to the patient atherapeutically effective amount of a compound as described herein. Anillustrative allergic disease is asthma.

Formula I compounds also are useful in a method of treating a patientafflicted with an autoimmune disease, comprising administering to thepatient a therapeutically effective amount of the compound. In variousembodiments, the autoimmune disease is chosen from multiple sclerosis,type I diabetes, inflammatory bowel diseases, Crohn's disease,ulcerative colitis, Grave's disease, Addison's disease, dermatomyositis,myasthenia gravis, systemic lupus erythematosus, scleroderma, andpsoriasis. An exemplary autoimmune disease is multiple sclerosis. Inaccordance with some embodiments, multiple sclerosis comprises one ormore progressive forms of multiple sclerosis as well as the remittingrelapsing form of the disease.

Additional embodiments include a method of treating a patient afflictedwith atherosclerosis or pulmonary arterial hypertension. The methodcomprises administering to the patient a therapeutically effectiveamount of a compound as described herein.

LITERATURE CITED IN THE PRESENT DISCLOSURE

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EXAMPLES

The present disclosure will be more fully understood by reference to thefollowing examples. The examples should not, however, be construed aslimiting the scope of the present disclosure.

General Procedure 1: Suzuki-Miyaura Cross Coupling

To a round bottom flask a containing alkene (1.1 equiv) in THF was added9BBN (1.5 equiv) and then heated to reflux until consumption of alkeneas monitored by TLC (30-60 minutes). Aryl iodide (1 equiv) andPd(dppf)Cl₂ (0.05 equiv) were then added to the mixture, followed bydropwise addition of a 3M KOH(.q) solution (3 equiv). The resultingmixture was then heated to reflux until consumption of aryl iodide asmonitored by TLC (2-6 hours). Upon cooling to room temperature, thereaction mixture was filtered over a pad of celite, diluted in ethylacetate, and washed with a brine solution. The organic layer was thendried over sodium sulfate and concentrated in vacuo to afford the crudeproduct as a yellow oil, which was then purified by columnchromatography with an appropriate hexanes:ethyl acetate solvent systemto afford the pure product.

General Procedure 2: Amidoxime Synthesis A

To a round bottom flask containing ethanol was added 4-decylbenzonitrile(1 equiv), hydroxylamine hydrochloride (2 equiv), and triethylamine (3equiv) under ambient air. The reaction mixture was then heated to refluxuntil complete as monitored by TLC (1-4 hours). The resulting solutionwas allowed to cool to room temperature, followed by concentration invacuo, to afford the crude mixture as a solid. Purification by columnchromatography (0-20% ethyl acetate in dichloromethane) afforded thepure amidoxime product.

General Procedure 3: Amidoxime Synthesis B

To a round bottom flask containing ethanol:water (1:1) was addedbenzonitrile (1 equiv), hydroxylamine hydrochloride (2 equiv), andsodium carbonate (5 equiv) under ambient air. The reaction mixture wasthen heated to reflux until complete as monitored by TLC (1-6 hours).The resulting solution was allowed to cool to room temperature. A whiteprecipitate formed upon cooling which was vacuum filtered over a filterfrit and washed with water and ethanol. This afforded the pure amidoximeproduct.

General Procedure 4: 1,2,4-Oxadiazole Synthesis

Amidoxime (1 equiv), N-Boc protected amino acid (1.1 equiv), and DIEA(1.8 equiv) were added to a round bottom flask containing DMF at roomtemperature. HCTU (1.1 equiv) was then added and the resulting mixturewas heated to 100° C. until completion as monitored by TLC (6-16 hours).Upon cooling to room temperature, the resulting mixture was diluted inethyl acetate and washed with a saturated lithium bromide solution. Theresulting aqueous layer was then extracted with ethyl acetate. Theorganic layers were then combined and washed with a brine solution,followed by drying over anhydrous sodium sulfate. Concentration in vacuoafforded the crude product, which was then purified by columnchromatography using the appropriate ethyl acetate:hexanes solventsystem to afford the pure 1,2,4-oxadiazole product.

General Procedure 5: TFA Boc Deprotection

To a round bottom flask containing Boc-protected amine or dibocprotected guanidine compounds (1 equiv) dissolved in dichloromethane wasadded TFA (30 equiv). The resulting solution was allowed to stir untilconsumption of starting material as monitored by TLC (1-6 hours).Concentration in vacuo and filtration of the resulting off-white solid,followed by washing with diethyl ether afforded the corresponding TFAsalts.

General Procedure 6: HCl Boc Deprotection A

To a 6-dram vial containing boc protected amine (1 equiv) was addedhydrogen chloride (30-100 equiv, 4M in dioxane). The resulting mixturewas allowed to stir until consumption of starting material as monitoredby TLC (0.5-6 hours). A thick white precipitate forms during the courseof the reaction. This precipitate was vacuum filtered over a filter fritand washed with diethyl ether to afford the pure product as an HCl salt.

General Procedure 7: Microwave Assisted Cyclization of Primary Amines

To a microwave vial were added primary amine salt (1 equiv), water,K₂CO₃ (1.1 equiv), and dibromoalkane at rt. The vial was then heated to120° C. for 20 minutes in a CEM Discover SP Microwave Synthesizer. Thereaction was then extracted with ethyl acetate and washed with a 50:50brine:10% NaOH solution. The organic layer was then dried over anhydroussodium sulfate and concentrated in vacuo to afford the crude product asa colorless oil. The crude product was then subjected to flashchromatography in an appropriate methanol:dichloromethane solventsystem. The chromatographed material was then dissolved in methanolicHCl and concentrated in vacuo to afford the cyclic amine HCl salt.

General Procedure 8: HCTU Coupling

To a 6-dram vial containing N-boc-amino acid (1.1 equiv) was added DMF(0.2 M), DIEA (1.8 equiv) and HCTU (1.1 equiv). The resulting mixturewas allowed to stir at rt for 5 minutes, followed by addition of anilinederivative (1 equiv). The resulting mixture was allowed to stir at rtuntil consumption of aniline as monitored by TLC (1-4 hours). Theresulting reaction mixture was diluted in ethyl acetate and washed witha saturated lithium bromide solution. The organic layer was then driedover anhydrous sodium sulfate and concentrated in vacuo to afford anorange oil which was then subjected to flash chromatography with anappropriate ethyl acetate in dichloromethane solvent system to affordthe pure product.

General Procedure 9: 1,2,4-Oxadiazole Synthesis

Amidoxime (1 equiv), acyl chloride or carboxylic acid (1.1 equiv), andDIEA (1.1 equiv) were added to a round bottom flask containing THF atroom temperature. The resulting mixture was heated to 60° C. for 12hours. Concentration in vacuo afforded the crude product, which was thenpurified by column chromatography using the appropriate ethylacetate:hexanes solvent system to afford the pure 1,2,4-oxadiazoleproduct.

General Procedure 10: Amide Synthesis

Ester (1 equiv) and primary amine (1.5 equiv) were added to a roundbottom flask followed by 1:1 MeOH:DCM. The resulting reaction mixturewas stirred at room temperature for 2 hours. Concentration in vacuoafforded the crude product, which was then purified by columnchromatography using the appropriate ethyl acetate:hexanes solventsystem to afford the pure product.

General Procedure 11: Removal of Fmoc Protecting Group

To a round bottom flask containing a stir bar and an Fmoc-protectedamine was added morpholine (60 equiv) and dichloromethane. The reactionwas allowed to stir overnight for 18 hours. Upon completion of thereaction, the mixture was concentrated under reduced pressure andsubjected to silica gel chromatography with an appropriate ethylacetate:hexanes solvent system to afford the pure product.

N′-hydroxy-4-iodobenzimidamide (3a)

Synthesized according to General Procedure 2. Isolated as a mixture ofZ:E (20:1). White solid, 560 mg (76%) yield. ¹H NMR (400 MHz, CDCl₃) δ7.54 (d, J=8.2 Hz, 2H), 7.20 (d, J=8.2 Hz, 2H), 4.89 (brs, 2H), 2.62 (t,J=7.7 Hz, 2H), 1.66-1.55 (m, 2H), 1.37 (m, 14H), 0.88 (t, J=6.7 Hz, 3H).

(Z)-2-(4-bromophenyl)-N′-hydroxyacetimidamide (3b)

Synthesized according to General Procedure 3. White solid (62%, 542 mg).¹H NMR (400 MHz, CD₃OD) δ 7.44 (d, J=8.4 Hz, 2H), 7.23 (d, J=8.4 Hz,2H), 3.34 (s, 2H). ¹³C NMR (101 MHz, CD₃OD) δ 155.5, 137.7, 132.5,131.6, 121.5, 37.5. HRMS: (ESI) [M+H]+ calc. for C₈H₁₀BrN₂O, 228.9971,observed, 228.9977.

(Z)-3-(4-bromophenyl)-N′-hydroxypropanimidamide (3c)

Synthesized according to General Procedure 3. White solid (41%, 352 mg).¹H NMR (400 MHz, CD₃OD) δ 7.40 (d, J=8.2 Hz, 2H), 7.15 (d, J=8.2 Hz,2H), 2.84 (d, J=7.7 Hz, 2H), 2.34 (d, J=7.7 Hz, 2H). ¹³C NMR (101 MHz,CD₃OD) δ 156.4, 141.5, 132.4, 131.5, 120.8, 33.8, 33.7. HRMS: (ESI)[M+H]+ calc. for C₉H₁₂BrN₂O, 243.0128, observed, 243.0135.

(Z)—N′-hydroxy-4-(nonyloxy)benzimidamide (3d)

Synthesized according to General Procedure 3. White solid (35%, 320 mg).¹H NMR (400 MHz, CDCl₃) δ 8.76 (s, 1H), 7.64 (d, J=8.9 Hz, 2H), 6.91 (d,J=8.8 Hz, 2H), 5.38 (s, 2H), 4.01 (t, J=6.5 Hz, 2H), 1.82-1.72 (m, 2H),1.53-1.43 (m, 2H), 1.42-1.22 (m, 10H), 0.88 (t, J=6.8 Hz, 3H). ¹³C NMR(101 MHz, CDCl₃) δ 160.9, 152.0, 127.6, 126.8, 114.8, 68.6, 32.6, 30.3,30.1, 30.0, 30.0, 26.8, 23.3, 14.4. HRMS: (ESI) [M+H]+ calc. forC₁₆H₂₇N₂O₂, 279.2073, observed, 279.2061.

(Z)—N′-hydroxy-4-(nonyloxy)-3-(trifluoromethyl)benzimidamide (3e)

Synthesized according to General Procedure 3. White solid (89%, 616 mg).¹H NMR (400 MHz, Acetone-d₆) δ 9.0 (s, 1H), 8.0 (d, J=2.3 Hz, 1H), 7.9(dd, J=8.7, 2.0 Hz, 1H), 7.2 (d, J=8.7 Hz, 1H), 5.6 (s, 2H), 4.2 (t,J=6.3 Hz, 2H), 1.9-1.8 (m, 2H), 1.6-1.5 (m, 2H), 1.4-1.2 (m, 10H), 0.9(t, J=6.8 Hz, 3H). ¹³C NMR (101 MHz, Acetone-d₆) δ 157.6 (d, J=1.6 Hz),150.1, 130.7, 125.5, 124.0 (q, J=5.4 Hz), 123.9 (q, J=271.7 Hz), 117.7(q, J=30.6 Hz), 112.9, 68.7, 31.7, 29.0, 28.8, 25.6, 22.4, 13.4. HRMS:(ESI) [M+H]+ calc. for C₁₇H₂₆N₂OF₃, 347.1946, observed, 347.1944.

6-(heptyloxy)-N′-hydroxy-2-naphthimidamide (3f)

Synthesized according to General Procedure 3. Purified by silica plug(dichloromethane wash followed by elution with 100% ethyl acetate). Greysolid (93%, 2.1 g). ¹H NMR (400 MHz, acetone-d₆) δ 8.98 (s, 1H), 8.13(d, J=1.7 Hz, 1H), 7.85 (dd, J=8.7, 1.8 Hz, 1H), 7.81 (d, J=8.9 Hz, 1H),7.74 (d, J=8.7 Hz, 1H), 7.29 (d, J=8.7 Hz, 1H), 7.16 (dd, J=8.9, 2.5 Hz,1H), 5.56 (s, 2H), 4.12 (t, J=6.5 Hz, 2H), 1.89-1.79 (m, 2H), 1.57-1.47(m, 2H), 1.45-1.28 (m, 7H), 0.90 (t, J=6.8 Hz, 3H). ¹³C NMR (101 MHz,acetone-d₆) δ 158.6, 152.1, 136.1, 130.6, 129.6, 129.3, 127.3, 125.0,124.8, 120.1, 107.4, 69.6, 32.6, 30.0, 29.8, 26.8, 23.3, 14.4. HRMS:(ESI) [M+H]+ calc. for C₁₈H₂₅N₂O₂, 301.1911, observed, 301.1912.

tert-butyl4-(3-(4-decylphenyl)-1,2,4-oxadiazol-5-yl)piperidine-1-carboxylate (4a)

Synthesized by General Procedure 4. Purified by silica chromatography(14% EtOAc in hexanes). Yellow oil, 335 mg (76%) yield. ¹H NMR (400 MHz,CDCl₃) δ 7.97 (d, J=8.3 Hz, 2H), 7.27 (d, J=8.3 Hz, 2H), 4.11 (brs, 2H),3.18-3.09 (m, 1H), 298 (t, J=11.6 Hz, 1H), 2.64 (t, J=7.7 Hz, 2H),2.14-2.05 (m, 2H), 1.94-1.82 (m, 2H), 1.67-1.56 (m, 2H), 1.48 (brs, 9H),1.37-1.19 (m, 14H), 0.87 (t, J=6.9 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ181.0, 168.2, 154.5, 146.4, 128.8, 127.3, 124.2, 79.7, 42.8, 35.9, 34.4,31.9, 31.2, 29.6, 29.6, 29.5, 29.3, 29.2, 29.1, 28.4, 22.7, 14.1. HRMS:(ESI) [M+H]+ calc. for C₂₈H₄₄N₃O₃, 470.3377, observed, 470.3369.

tert-butyl(R)-(1-(3-(4-decylphenyl)-1,2,4-oxadiazol-5-yl)-3-methylbutan-2-yl)carbamate(4b)

Synthesized according to General Procedure 4. Purified by silicachromatography (18% EtOAc in hexanes). Light yellow solid, 125 mg (37%)yield. ¹H NMR (400 MHz, CDCl₃) δ 7.97 (d, J=8.0 Hz, 2H), 7.27 (d, J=8.0Hz, 2H), 4.91 (d, J=9.4 Hz, 1H), 3.97-3.87 (m, 1H), 3.17-3.06 (m, 2H),2.65 (t, J=7.6 Hz, 2H), 1.85-1.74 (m, 1H), 1.68-1.57 (m, 2H), 1.39 (brs,9H), 1.36-1.19 (m, 14H), 1.00-0.94 (m, 6H), 0.87 (t, J=6.6 Hz, 3H). ¹³CNMR (100 MHz, CDCl₃) δ 177.3, 168.2, 155.4, 146.5, 128.9, 127.4, 124.1,79.4, 53.9, 35.9, 31.9, 31.5, 31.2, 29.9, 29.6, 29.6, 29.5, 29.3, 29.2,28.3, 22.7, 19.4, 18.4, 14.1. HRMS: (ESI) [M+H]+ calc. for C₂₈H₄₆N₃O₃,472.3534, observed, 472.3537.

tert-butyl (2-(3-(4-decylphenyl)-1,2,4-oxadiazol-5-yl)ethyl)carbamate(4c)

Synthesized according to General Procedure 4. Purified by silicachromatography (20% EtOAc in hexanes). Light yellow solid, 155 mg (50%)yield. ¹H NMR (400 MHz, CDCl₃) δ 7.97 (d, J=8.1 Hz, 2H), 7.27 (d, J=8.1Hz, 2H), 5.27 (brs, 1H), 3.69-3.62 (m, 2H) 3.12 (t, J=6.0 Hz, 2H), 2.65(t, J=7.7 hz, 2H), 1.68-1.58 (m, 2H), 1.43 (brs, 9H), 1.37-1.21 (m,14H), 0.89 (t, J=6.8 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 177.8, 168.3,155.8, 146.6, 129.0, 127.4, 124.1, 79.7, 37.3, 36.0, 32.0, 31.3, 29.7,29.6, 29.5, 29.4, 29.3, 28.4, 27.6, 22.8, 14.2. HRMS: (ESI) [M+H]+ calc.for C₂₅H₄₀N₃O₃, 430.3064, observed, 430.3076.

tert-butyl(S)-(1-(3-(4-decylphenyl)-1,2,4-oxadiazol-5-yl)propan-2-yl)carbamate(4d)

Synthesized by General Procedure 4. Purified by silica chromatography(15% EtOAc in hexanes). Yellow solid, 110 mg (46%) yield. ¹H NMR (400MHz, CDCl₃) δ 7.98 (d, J=8.2 Hz, 2H), 7.28 (d, J=8.2 Hz, 2H), 5.02-4.90(m, 1H), 4.29-4.17 (m, 1H), 3.15 (d, J=5.8 Hz, 2H), 2.66 (t, J=7.7 Hz,2H), 1.68-1.57 (m, 2H), 1.43 (brs, 9H), 1.36-1.20 (m, 17H), 0.88 (t,J=6.8 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 177.0, 168.3, 155.0, 146.6,129.0, 127.5, 124.2, 79.7, 44.5, 36.0, 33.5, 32.0, 31.3, 29.7, 29.7,29.6, 29.4, 20.3, 28.4, 22.8, 20.30, 14.2. HRMS: (ESI) [M+Na]+ calc. forC₂₆H₄₂N₃O₃, 444.3221, observed, 3244.

(t)-tert-butyl3-((3-(4-decylphenyl)-1,2,4-oxadiazol-5-yl)methyl)morpholine-4-carboxylate(4e)

Synthesized according to General Procedure 4. Purified by silicachromatography (25% ethyl acetate in hexanes). Yellow solid (57%, 151mg). ¹H NMR (400 MHz, CDCl₃) δ 7.94 (d, J=8.0 Hz, 2H), 7.24 (d, J=7.9Hz, 2H), 4.59-4.33 (m, 1H), 4.02-3.70 (m, 3H), 3.63 (dd, J=11.8, 3.2 Hz,1H), 3.54-3.18 (m, 4H), 2.62 (t, J=7.7 Hz, 2H), 1.61 (p, J=7.2 Hz, 2H),1.41-1.15 (m, 23H), 0.84 (t, J=6.8 Hz, 3H). ¹³C NMR (101 MHz, CDCl₃) δ176.9, 168.4, 154.1, 146.4, 128.9, 127.4, 124.2, 80.5, 68.9, 66.9, 50.4,48.8, 40.0, 38.5, 36.0, 31.9, 31.3, 29.6, 29.6, 29.5, 29.4, 29.3, 28.2,26.4, 22.7, 14.2. HRMS: (ESI) [M]+ calc. for C₂₈H₄₄N₃O₄, 486.3326,observed, 486.3342.

tert-butyl(R)-2-(3-(4-decylphenyl)-1,2,4-oxadiazol-5-yl)morpholine-4-carboxylate(4f)

Synthesized according to General Procedure 4. Purified by silicachromatography (20 EtOAc in hexanes). Yellow oil, 246 mg (64%) yield. ¹HNMR (400 MHz, CDCl₃) δ 7.97 (d, J=8.2 Hz, 2H), 7.25 (d, J=8.2 Hz, 2H),4.82-4.77 (m, 1H), 4.44-4.11 (m, 1H), 4.05 (d, J=11.1 Hz, 1H), 3.84 (d,J=13.3 Hz, 1H), 3.70 (t, J=10 Hz, 1H), 3.38 (brs, 1H), 3.23-3.13 (m,1H), 2.61 (t, J=7.7 Hz, 2H), 1.65-1.54 (m, 2H), 1.45 (brs, 9H),1.34-1.15 (m, 14H), 0.84 (t, J=6.8 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ175.3, 168.4, 154.3, 146.7, 128.9, 127.5, 123.6, 80.7, 70.0, 66.5, 46.3,43.1, 36.0, 31.9, 31.2, 29.6, 29.6, 29.5, 29.3, 29.3, 28.3, 22.7, 14.1.HRMS: (ESI) [M+H]+ calc. for C₂₇H₄₂N₃O₄, 472.3175, observed, 472.3204.

tert-butyl((1S,3R)-3-(3-(4-decylphenyl)-1,2,4-oxadiazol-5-yl)cyclopentyl)carbamate(4g)

Synthesized according to General Procedure 4. Purified by silicachromatography (20% EtOAc in hexanes). Yellow solid, 213 mg (63%) yield.¹H NMR (400 MHz, CDCl₃) δ 7.98 (d, J=8.2 Hz, 2H), 7.27 (d, J=8.2 Hz,2H), 5.67 (brs, 1H), 4.23 (brs, 1H), 3.59-3.48 (m, 1H), 2.66 (t, J=7.7Hz, 2H), 2.53-2.43 (m, 1H), 2.29-1.91 (m, 4H), 1.85-1.74 (m, 1H),1.68-1.58 (m, 2H), 1.47 (brs, 9H), 1.38-1.19 (m, 14H), 0.88 (t, J=6.8Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 183.6, 168.2, 155.5, 146.7, 129.0,127.5, 124.1, 79.2, 52.0, 38.1, 36.1, 35.2, 33.4, 32.0, 31.4, 30.1,29.7, 29.7, 29.6, 29.4, 29.4, 28.6, 28.6, 22.8, 14.3. HRMS: (ESI) [M+H]+calc. for C₂₈H₄₄N₃O₃, 470.3377, observed, 470.3372.

tert-butyl (3-(3-(4-decylphenyl)-1,2,4-oxadiazol-5-yl)propyl)carbamate(4h)

Synthesized according to General Procedure 4. Purified by silicachromatography (20% EtOAc in hexanes). Yellow oil, 260 mg (65%) yield.¹H NMR (400 MHz, CDCl₃) δ 7.97 (d, J=8.2 Hz, 2H), 7.26 (d, J=8.2 Hz,2H), 5.07 (brs, 1H), 3.32-3.22 (m, 2H), 2.97 (t, J=7.5 Hz, 2H), 2.64 (t,J=7.7 Hz, 2H), 2.11-2.02 (m, 2H), 1.67-1.57 (m, 2H), 1.43 (brs, 9H),1.36-1.20 (m, 14H), 0.88 (t, J=6.8 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ179.2, 168.2, 156.0, 146.4, 128.9, 127.3, 124.2, 79.2, 39.8, 35.9, 31.9,31.2, 29.6, 29.6, 29.5, 29.3, 29.3, 28.4, 26.9, 24.1, 22.7, 14.1. HRMS:(ESI) [M+Na]+ calc. for C₂₆H₄₁N₃NaO₃, 466.3040, observed, 466.3034.

tert-butyl ((3-(4-decylphenyl)-1,2,4-oxadiazol-5-yl)methyl)carbamate

Synthesized according to General Procedure 4. Purified by silicachromatography (15% EtOAc in hexanes). White solid, 281 mg (75%) yield.¹H NMR (400 MHz, CDCl₃) δ 7.95 (d, J=8.0 Hz, 2H), 7.26 (d, J=8.0 Hz,2H), 5.59 (brs, 1H), 4.66-4.55 (m, 2H), 2.64 (t, J=7.7 Hz, 2H),1.67-1.57 (m, 2H), 1.46 (brs, 9H), 1.36-1.20 (m, 14H), 0.88 (t, J=6.7Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 176.5, 168.4, 155.6, 146.7, 128.9,127.4, 123.9, 80.6, 37.2, 36.0, 32.0, 31.3, 29.7, 29.6, 29.5, 29.4,29.4, 29.3, 28.3, 22.7, 14.2. HRMS: (ESI) [M+H]+ calc. for C₂₄H₃₈N₃O₃,416.2908, observed, 416.2925.

tert-butyl(3-(3-(4-decylphenyl)-1,2,4-oxadiazol-5-yl)-2-hydroxypropyl)carbamate

Synthesized according to General Procedure 4. Purified by silicachromatography (40% EtOAc in hexanes). Yellow solid, 452 mg (60%) yield.¹H NMR (400 MHz, CDCl₃) δ 7.94 (d, J=8.0 Hz, 2H), 7.26 (d, J=8.0 Hz,2H), 5.30 (brs, 1H), 4.30 (brs, 2H), 3.49-3.41 (m, 1H), 3.32-3.22 (m,1H), 3.14-3.05 (m, 2H), 2.64 (t, J=7.7 Hz, 2H), 1.66-1.58 (m, 2H), 1.44(brs, 9H), 1.36-1.20 (m, 14H), 0.88 (t, J=6.8 Hz, 3H). ¹³C NMR (100 MHz,CDCl₃) δ 177.3, 168.1, 156.9, 146.7, 129.0, 127.4, 123.8, 80.0, 68.5,45.7, 36.0, 32.0, 31.7, 31.3, 29.7, 29.7, 29.6, 29.4, 29.3, 28.4, 22.8,14.2. HRMS: (ESI) [M+H]+ calc. for C₂₆H₄₂N₃O₄, 460.3170, observed,460.3169.

tert-butyl4-((3-(4-decylphenyl)-1,2,4-oxadiazol-5-yl)methyl)piperazine-1-carboxylate(4k)

Synthesized according to General Procedure 4. Purified by silicachromatography (35% ethyl acetate in hexanes). White solid (63%, 248mg). ¹H NMR (400 MHz, CDCl₃) δ 7.99 (d, J=8.2 Hz, 2H), 7.29 (d, J=8.2Hz, 2H), 3.93 (s, 2H), 3.5 (t, J=5.0 Hz, 4H), 2.66 (t J=7.7 Hz, 2H),2.60 (t J=5.0 Hz, 4H), 1.64 (p, J=7.3 Hz, 2H), 1.45 (s, 9H), 1.38-1.19(m, 14H), 0.87 (t, J=6.7 Hz, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 175.8,168.5, 154.7, 146.8, 129.1, 127.6, 124.0, 80.0, 53.2, 52.7, 43.6, 36.1,32.0, 31.4, 29.7, 29.7, 29.6, 29.5, 29.4, 28.5, 22.8, 14.3. HRMS: (ESI)[M+H]+ calc. for C₂₈H₄₅N₄O₃, 485.3486, observed, 485.3479.

tert-butyl(3-(3-(4-(benzyloxy)phenyl)-1,2,4-oxadiazol-5-yl)propyl)carbamate (41)

Synthesized according to General Procedure 4. Purified by silicachromatography (35% ethyl acetate in hexanes). White solid (31%, 585mg). ¹H NMR (400 MHz, CDCl₃) δ 8.00 (d, J=8.9 Hz, 2H), 7.49-7.31 (m,5H), 7.05 (d, J=8.9 Hz, 2H), 5.12 (s, 2H), 4.83 (brs, 1H), 3.35-3.22 (m,2H), 2.98 (t, J=7.5 Hz, 2H), 2.06 (p, J=7.1 Hz, 2H), 1.44 (s, 9H). ¹³CNMR (101 MHz, CDCl₃) δ 179.2, 168.1, 161.2, 156.1, 136.5, 129.1, 128.8,128.3, 127.6, 119.6, 115.2, 79.5, 70.2, 39.9, 28.5, 27.0, 24.2. HRMS:(ESI) [M+H]+ calc. for C₂₃H₂₈N₃O₄, 410.2074, observed, 410.2055.

tert-butyl (3-(3-(3-decylphenyl)-1,2,4-oxadiazol-5-yl)propyl)carbamate(4m)

Synthesized according to General Procedure 4. Passed through a silicacolumn silica (ethyl acetate in hexanes) to afford crude mixture whichwas carried forward without further purification.

tert-butyl(E)-(3-(3-(4-decylphenyl)-1,2,4-oxadiazol-5-yl)allyl)carbamate (4n)

Synthesized according to General Procedure 4. Purified by silicachromatography (15% ethyl acetate in hexanes). White solid (74%, 143mg). ¹H NMR (400 MHz, CDCl₃) δ 7.98 (d, J=8.2 Hz, 2H), 7.28 (d, J=8.1Hz, 2H), 7.09 (dt, J=16.1, 4.9 Hz, 1H), 6.58 (d, J=16.1 Hz, 1H), 5.00(brs, 1H), 4.03 (brs, 2H), 2.65 (t, J=7.7 Hz, 2H), 1.63 (p, J=7.1 Hz,2H), 1.47 (s, 9H), 1.37-1.19 (m, 14H), 0.88 (t, J=6.7 Hz, 3H). ¹³C NMR(101 MHz, CDCl₃) δ 174.2, 168.7, 155.7, 146.6, 143.1, 129.0, 127.4,124.2, 113.5, 80.0, 41.9, 36.0, 32.0, 31.3, 29.7, 29.7, 29.6, 29.4,29.3, 28.4, 22.8, 14.2. HRMS: (ESI) [M+H]+ calc. for C₂₆H₄₀N₃O₃,442.3070, observed, 442.3063.

tert-butyl(3-(3-(4-decylphenyl)-1,2,4-oxadiazol-5-yl)propyl)(methyl)carbamate (4o)

Synthesized according to General Procedure 4. Purified by silicachromatography (15% ethyl acetate in hexanes). Yellow oil (54%, 319 mg).¹H NMR (400 MHz, CDCl₃) δ 7.96 (d, J=8.2 Hz, 2H), 7.28 (d, J=8.2 Hz,2H), 3.38 (t, J=6.9 Hz, 2H), 2.94 (t, J=7.6 Hz, 2H), 2.88 (s, 3H), 2.65(t, J=7.7 Hz, 2H), 2.10 (p, J=7.3 Hz, 2H), 1.63 (p, J=7.5 Hz, 2H), 1.44(s, 9H), 1.38-1.19 (m, 14H), 0.87 (t, J=6.8 Hz, 3H). ¹³C NMR (101 MHz,CDCl₃) δ 179.0, 168.3, 146.4, 128.9, 127.3, 124.2, 79.3, 47.7, 35.9,34.2, 31.9, 31.2, 29.6, 29.6, 29.5, 29.3, 29.2, 28.4, 24.7, 23.9, 22.7,14.1. HRMS: (ESI) [M+H]+ calc. for C₂₇H₄₄N₃O₃, 458.3377, observed,458.3372.

1-((tert-butoxycarbonyl)amino)-3-(3-(4-decylphenyl)-1,2,4-oxadiazol-5-yl)propan-2-ylacetate (4p)

To a 6-dram vial containing 4j was added acetic anhydride (51 equiv) andTEA (9 equiv) and the mixture was allowed to stir at rt for 30 minutes.The mixture was then diluted with ethyl acetate and washed with asaturated sodium carbonate solution followed by a brine solution. Theorganic layer was then concentrated in vacuo and subjected to flashchromatography (25% ethyl acetate in hexanes) which afforded a crudemixture which was carried forward without any further purification.

tert-butyl (3-(3-(4-decylphenyl)-1,2,4-oxadiazol-5-yl)benzyl)carbamate(4q)

Synthesized according to General Procedure 4. Purified by silicachromatography (17% ethyl acetate in hexanes). Yellow solid (59%, 232mg). ¹H NMR (400 MHz, CDCl₃) δ 8.14-8.09 (m, 2H), 8.07 (d, J=8.2 Hz,2H), 7.56-7.49 (m, 2H), 7.32 (d, J=8.3 Hz, 2H), 4.99 (brs, 1H), 4.43 (d,J=6.2 Hz, 2H), 2.68 (t, J=7.5 Hz, 2H), 1.65 (p, J=7.4 Hz, 2H), 1.49 (s,9H), 1.39-1.20 (m, 14H), 0.87 (t, J=6.8 Hz, 3H). ¹³C NMR (101 MHz,CDCl₃) δ 175.5, 169.1, 156.0, 146.7, 140.5, 131.8, 129.6, 129.1, 127.6,127.2, 127.0, 124.8, 124.4, 80.0, 44.4, 36.1, 32.1, 31.4, 29.8, 29.7,29.6, 29.5, 29.4, 28.5, 22.8, 14.3. HRMS: (ESI) [M+H]+ calc. forC₃₀H₄₂N₃O₃, 492.3221, observed, 492.3209.

tert-butyl((±)-cis-3-(3-(4-decylphenyl)-1,2,4-oxadiazol-5-yl)cyclohexyl)carbamate(4r)

Synthesized according to General Procedure 4. Purified by silicachromatography (12% ethyl acetate in hexanes). Yellow solid (72%, 314mg). ¹H NMR (400 MHz, CDCl₃) δ 7.96 (d, J=8.2 Hz, 2H), 7.27 (d, J=8.2Hz, 2H), 4.58 (s, 1H), 3.61 (s, 1H), 3.10 (dt, J=11.6, 5.9 Hz, 1H),2.71-2.58 (m, 2H), 2.48 (d, J=12.4 Hz, 1H), 2.15 (d, J=9.4 Hz, 1H), 2.05(d, J=12.7 Hz, 1H), 1.99-1.90 (m, 1H), 1.70-1.49 (m, 6H), 1.45 (s, 9H),1.38-1.13 (m, 14H), 0.87 (t, J=6.8 Hz, 3H). ¹³C NMR (101 MHz, CDCl₃) δ181.5, 168.2, 155.0, 146.4, 128.9, 127.3, 124.2, 79.3, 48.8, 36.6, 35.9,35.5, 32.6, 31.9, 31.2, 29.6, 29.6, 29.5, 29.3, 29.2, 28.4, 24.1, 22.7,14.1. HRMS: (ESI) [M+Na]+ calc. for C₂₉H₄₅N₃NaO₃, 506.3353, observed,506.3337.

tert-butyl((±)-trans-3-(3-(4-decylphenyl)-1,2,4-oxadiazol-5-yl)cyclohexyl)carbamate(4s)

Synthesized according to General Procedure 4. Purified by silicachromatography (12% ethyl acetate in hexanes). Yellow solid (73%, 318mg). ¹H NMR (400 MHz, CDCl₃) δ 7.97 (d, J=8.2 Hz, 2H), 7.27 (d, J=8.3Hz, 2H), 4.63 (brs, 1H), 3.95 (brs 1H), 3.29 (brs, 1H), 2.65 (d, J=7.7Hz, 2H), 2.22-1.54 (m, 10H), 1.45 (s, 9H), 1.28 (d, J=19.6 Hz, 14H),0.87 (t, J=6.8 Hz, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 181.9, 168.4, 155.2,146.5, 129.0, 127.5, 124.4, 79.5, 45.5, 36.1, 34.5, 32.2, 32.0, 31.4,30.9, 29.7, 29.7, 29.6, 29.5, 29.4, 29.2, 28.6, 22.8, 20.6, 14.2. HRMS:(ESI) [M+Na]+ calc. for C₂₉H₄₅N₃NaO₃, 506.3353, observed, 506.3336.

tert-butyl (3-(3-(4-bromobenzyl)-1,2,4-oxadiazol-5-yl)propyl)carbamate(4t)

Synthesized according to General Procedure 4. Purified by silicachromatography (35% ethyl acetate in hexanes). Yellow oil (68%, 292 mg).¹H NMR (400 MHz, CDCl₃) δ 7.44 (d, J=8.4 Hz, 2H), 7.19 (d, J=8.5 Hz,2H), 4.65 (s, 1H), 3.99 (s, 2H), 3.21 (q, J=6.3 Hz, 2H), 2.89 (t, J=7.6Hz, 2H), 1.97 (p, J=7.0 Hz, 2H), 1.43 (s, 9H). ¹³C NMR (101 MHz, CDCl₃)δ 179.7, 169.1, 156.0, 134.5, 132.0, 130.8, 121.3, 79.6, 39.8, 31.9,28.5, 27.0, 24.1. HRMS: (ESI) [M+H]+ calc. for C₁₇H₂₃BrN₃O₃, 418.0737,observed, 418.0746.

tert-butyl (3-(3-(4-nonylbenzyl)-1,2,4-oxadiazol-5-yl)propyl)carbamate(4u)

Synthesized according to General Procedure 1 from 4ag. Purified bysilica chromatography (25% ethyl acetate in hexanes). Colorless oil(48%, 149 mg). ¹H NMR (400 MHz, CDCl₃) δ 7.21 (d, J=8.0 Hz, 2H), 7.12(d, J=8.1 Hz, 2H), 4.69 (s, 1H), 4.00 (s, 2H), 3.20 (q, J=6.2 Hz, 2H),2.88 (t, J=7.6 Hz, 2H), 2.56 (d, J=7.7 Hz, 2H), 1.97 (p, J=7.0 Hz, 2H),1.58 (p, J=7.4 Hz, 2H), 1.43 (s, 9H), 1.27 (d, J=14.6 Hz, 12H), 0.86 (t,3H). ¹³C NMR (101 MHz, CDCl₃) δ 179.4, 169.7, 156.0, 141.9, 132.7,128.9, 128.9, 79.5, 39.8, 35.7, 32.0, 32.0, 31.6, 29.7, 29.6, 29.5,29.4, 28.5, 27.0, 24.1, 22.8, 14.2. HRMS: (ESI) [M+Na]+ calc. forC₂₆H₄₁N₃O₃Na, 466.3040, observed, 466.3049.

tert-butyl(3-(3-(4-bromophenethyl)-1,2,4-oxadiazol-5-yl)propyl)carbamate (4v)

Synthesized according to General Procedure 4. Purified by silicachromatography (35% ethyl acetate in hexanes). Yellow oil (76%, 322 mg).¹H NMR (400 MHz, CDCl₃) δ 7.40 (d, J=8.3 Hz, 2H), 7.08 (d, J=8.3 Hz,2H), 4.71 (s, 1H), 3.22 (q, J=6.2 Hz, 2H), 3.00 (q, J=3.1, 2.2 Hz, 4H),2.90 (t, J=7.5 Hz, 2H), 1.99 (p, J=7.1 Hz, 2H), 1.43 (s, 9H). ¹³C NMR(101 MHz, CDCl₃) δ 179.3, 169.6, 156.1, 139.3, 131.7, 130.2, 120.3,79.6, 39.8, 32.5, 28.5, 27.7, 27.0, 24.0. HRMS: (ESI) [M+Na]+ calc. forC₁₈H₂₄BrN₃O₃Na, 432.0893, observed, 432.0894.

tert-butyl(3-(3-(4-octylphenethyl)-1,2,4-oxadiazol-5-yl)propyl)carbamate (4w)

Synthesized according to General Procedure 1 from 4ai. Purified bysilica chromatography (20% ethyl acetate in hexanes). Colorless oil(50%, 166 mg). ¹H NMR (400 MHz, CDCl₃) δ 7.16-7.06 (m, 4H), 4.72 (s,1H), 3.23 (q, J=6.3 Hz, 2H), 3.05-2.98 (m, 4H), 2.91 (t, J=7.5 Hz, 2H),2.56 (t, 2H), 2.01 (p, J=6.9 Hz, 2H), 1.58 (p, J=7.5 Hz, 2H), 1.44 (s,9H), 1.38-1.20 (m, 10H), 0.87 (d, J=6.8 Hz, 3H). ¹³C NMR (101 MHz,CDCl₃) δ 179.1, 170.1, 156.0, 141.1, 137.6, 128.7, 128.3, 79.5, 39.8,35.7, 32.8, 32.0, 31.7, 29.6, 29.5, 29.4, 28.5, 28.1, 27.0, 24.0, 22.8,14.2. HRMS: (ESI) [M+Na]+ calc. for C₂₆H₄₁N₃O₃Na, 466.3040, observed,466.3044.

tert-butyl(3-(3-(4-(nonyloxy)phenyl)-1,2,4-oxadiazol-5-yl)propyl)carbamate (4x)

Synthesized according to General Procedure 4. Purified by silicachromatography (15% ethyl acetate in hexanes). White solid (79%, 316mg). ¹H NMR (400 MHz, CDCl₃) δ 7.98 (d, J=9.0 Hz, 2H), 6.96 (d, J=9.0Hz, 2H), 4.81 (s, 1H), 4.00 (t, J=6.6 Hz, 2H), 3.28 (q, J=6.1 Hz, 2H),2.97 (t, J=7.4 Hz, 2H), 2.06 (p, J=7.0 Hz, 2H), 1.88-1.71 (m, 2H), 1.44(s, 11H), 1.36-1.26 (m, 10H), 0.87 (t, 3H). ¹³C NMR (101 MHz, CDCl₃) δ179.1, 168.2, 161.7, 156.1, 129.1, 119.1, 114.9, 68.3, 39.9, 32.0, 29.7,29.5, 29.4, 29.3, 28.5, 27.1, 26.2, 24.2, 22.8, 14.2. HRMS: (ESI) [M+H]+calc. for C₂₅H₄₀N₃O₄, 446.3013, observed, 446.3004.

tert-butyl(3-(3-(4-(nonyloxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)propyl)carbamate(4y)

Synthesized according to General Procedure 4. Purified by silicachromatography (20% ethyl acetate in hexanes). Yellow solid (57%, 260mg). ¹H NMR (400 MHz, CDCl₃) δ 1H NMR (400 MHz, Chloroform-d) δ 8.3 (d,J=1.9 Hz, 1H), 8.2 (dd, J=8.7, 2.0 Hz, 1H), 7.1 (d, J=8.7 Hz, 1H), 4.7(s, 1H), 4.1 (t, J=6.4 Hz, 2H), 3.3 (q, J=6.1 Hz, 2H), 3.0 (t, J=7.5 Hz,2H), 2.1 (p, J=7.0 Hz, 2H), 1.9-1.8 (m, 2H), 1.4 (s, 11H), 1.4-1.2 (m,10H), 0.9 (t, J=6.8 Hz, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 179.6, 167.4,159.3, 132.5, 126.8 (q, J=5.3 Hz), 123.4 (q, J=272.6 Hz), 119.6 (q,J=31.4 Hz), 118.7, 113.0, 79.6, 69.2, 39.9, 32.0, 29.6, 29.3, 29.3,29.0, 28.5, 27.1, 25.9, 24.1, 22.8, 14.2. HRMS: (ESI) [M+H]+ calc. forC₂₆H₃₉F₃N₃O₄, 514.2887, observed, 514.2881.

tert-butyl(3-(3-(3-fluoro-4-(nonyloxy)phenyl)-1,2,4-oxadiazol-5-yl)propyl)carbamate(4z)

Synthesized according to General Procedure 4. Purified by silicachromatography (20% ethyl acetate in hexanes). Yellow solid (87%, 360mg). ¹H NMR (400 MHz, CD₃OD) δ 7.8-7.8 (m, 2H), 7.0 (t, J=8.6 Hz, 1H),4.8 (s, 1H), 4.1 (t, J=6.6 Hz, 2H), 3.3 (q, J=6.1 Hz, 2H), 3.0 (t, J=7.4Hz, 2H), 2.1 (p, J=7.0 Hz, 2H), 1.9-1.8 (m, 2H), 1.4 (s, 11H), 1.4-1.2(m, 10H), 0.9 (t, 3H). ¹³C NMR (101 MHz, CD₃OD) δ HRMS: (ESI) [M+H]+calc. for C₂₅H₃₉FN₃O₄, 464.2919, observed, 464.2910.

3-tert-butyl(3-(3-(6-(heptyloxy)naphthalen-2-yl)-1,2,4-oxadiazol-5-yl)propyl)carbamate(4aa)

Synthesized according to General Procedure 4. Purified by silicachromatography (20% ethyl acetate in hexanes). White solid (68%, 265mg). ¹H NMR (400 MHz, CDCl₃) δ 8.49 (s, 1H), 8.06 (dd, J=8.6, 1.7 Hz,1H), 7.82 (d, J=9.0 Hz, 1H), 7.78 (d, J=8.6 Hz, 1H), 7.18 (dd, J=8.9,2.5 Hz, 1H), 7.14 (d, J=2.4 Hz, 1H), 4.82 (s, 1H), 4.08 (t, J=6.6 Hz,2H), 3.35-3.23 (m, 2H), 3.01 (t, J=7.5 Hz, 2H), 2.10 (p, J=7.1 Hz, 2H),1.85 (p, J=6.7 Hz, 2H), 1.55-1.25 (m, 17H), 0.90 (t, J=6.8 Hz, 3H). ¹³CNMR (101 MHz, CDCl₃) δ 179.3, 168.6, 158.6, 156.1, 136.3, 130.4, 128.4,127.8, 127.5, 124.4, 121.8, 120.0, 106.7, 79.5, 68.2, 39.9, 29.3, 29.2,28.5, 27.1, 26.2, 24.2, 22.8, 14.2. HRMS: (ESI) [M+H]+ calc. forC₂₇H₃₈N₃O₄, 468.2857, observed, 468.2857.

tert-butyl(R)-3-(3-(6-(heptyloxy)naphthalen-2-yl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboxylate(4ab)

Synthesized according to General Procedure 4. Purified by silicachromatography (20% ethyl acetate in hexanes). Yellow solid (76%, 305mg). ¹H NMR (400 MHz, CDCl₃) δ 8.51 (brs, 1H), 8.07 (dd, J=8.6, 1.7 Hz,1H), 7.83 (d, J=8.9 Hz, 1H), 7.79 (d, J=8.6 Hz, 1H), 7.20 (dd, J=8.9,2.5 Hz, 1H), 7.15 (d, J=2.4 Hz, 1H), 4.09 (t, J=6.6 Hz, 2H), 3.97-3.44(m, 5H), 2.48-2.32 (m, 2H), 1.89-1.81 (m, 2H), 1.54-1.27 (m, 17H), 0.89(t, J=6.8 Hz, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 168.7, 158.7, 136.3,130.4, 128.5, 127.9, 127.6, 124.4, 121.7, 120.1, 106.7, 79.9, 68.3,49.3, 45.3, 36.8, 36.0, 31.9, 30.6, 29.8, 29.3, 29.2, 28.6, 26.2, 22.8,14.2. HRMS: (ESI) [M+H]+ calc. for C₂₈H₃₈N₃O₄, 480.2857, observed,480.2854.

3-(4-decylphenyl)-5-(piperidin-4-yl)-1,2,4-oxadiazole2,2,2-trifluoroacetate (5a)

Synthesized according to General Procedure 5. Purified by silicachromatography (7% MeOH in DCM). White solid, 330 mg (89%) yield. ¹H NMR(400 MHz, CD₃OD) δ 7.96 (d, J=8.3 Hz, 2H), 7.33 (d, J=8.3 Hz, 2H),3.56-3.43 (m, 3H), 3.27-3.16 (m, 2H), 2.68 (t, J=7.7 Hz, 2H), 2.48-2.35(m, 2H), 2.21-2.06 (m, 2H), 1.73-1.57 (m, 2H), 1.42-1.16 (m, 14H), 0.89(t, J=6.9 Hz, 3H). ¹³C NMR (100 MHz, CD₃OD) δ 181.5, 169.5, 148.1,130.1, 128.3, 125.3, 71.4, 44.0, 36.9, 33.1, 32.9, 32.5, 30.7, 30.6,30.5, 30.3, 27.2, 23.7, 14.5. HRMS: (ESI) [M+H]+ calc. for C₂₃H₃₆N₃O,370.2853, observed, 370.2826.

2-(3-(4-decylphenyl)-1,2,4-oxadiazol-5-yl)ethan-1-amine2,2,2-trifluoroacetate (5b)

Synthesized according to General Procedure 5. White solid, 110 mg (76%)yield. ¹H NMR (400 MHz, CD₃OD) δ 7.99 (d, J=8.2 Hz, 2H), 7.34 (d, J=8.2Hz, 2H), 3.52 (t, J=6.8 Hz, 2H), 3.38 (t, J=6.7 Hz, 2H), 2.68 (t, J=7.7Hz, 2H), 1.70-1.60 (m, 2H), 1.40-1.22 (m, 14H), 0.89 (t, J=6.8 Hz, 3H).¹³C NMR (100 MHz, CD₃OD) δ 177.6, 169.6, 148.2, 130.1, 28.4, 125.2,37.3, 36.9, 33.1, 32.5, 30.7, 30.6, 30.5, 30.3, 25.4, 23.7, 14.5. HRMS:(ESI) [M+H]+ calc. for C₂₀H₃₂N₃O, 330.254, observed, 330.2529.

(S)-1-(3-(4-decylphenyl)-1,2,4-oxadiazol-5-yl)propan-2-amine2,2,2-trifluoroacetate (5c)

Synthesized according to General Procedure 5. White solid, 76 mg (67%)yield. ¹H NMR (400 MHz, CD₃OD) δ 7.98 (d, J=8.1 Hz, 2H), 7.31 (d, J=8.1Hz, 2H), 4.03-3.87 (m, 1H), 3.36 (d, J=6.3 Hz, 2H), 2.66 (t, J=7.7 Hz,2H), 1.71-1.56 (m, 2H), 1.47 (d, J=6.7 Hz, 3H), 1.39-1.20 (m, 14H), 0.88(t, J=6.7 Hz, 3H). ¹³C NMR (100 MHz, CD₃OD) δ 177.0, 169.6, 163.1 (q,J=34.7 Hz), 148.1, 130.1, 128.4, 125.1, 46.6, 36.9, 33.1, 32.4, 32.0,30.7, 30.6, 30.5, 30.3, 23.7, 18.7, 14.5. HRMS: (ESI) [M+H]+ calc. forC₂₁H₃₄N₃O, 344.2696, observed, 344.2705.

(1S,3R)-3-(3-(4-decylphenyl)-1,2,4-oxadiazol-5-yl)cyclopentan-1-aminehydrochloride (5d)

Synthesized according to General Procedure 7. White solid, 122 mg (64%)yield. ¹H NMR (400 MHz, CD₃OD) δ 7.95 (d, J=8.3 Hz, 2H), 7.32 (d, J=8.3Hz, 2H), 3.82 (p, J=7.5 Hz, 1H), 3.66 (p, J=7.5 Hz, 1H), 2.78-2.64 (m,3H), 2.38-2.07 (m, 4H), 1.98-1.88 (m, 1H), 1.70-1.59 (m, 2H), 1.38-1.21(m, 14H), 0.89 (t, J=6.8 Hz, 3H). ¹³C NMR (100 MHz, CD₃OD) δ 183.1,169.4, 148.0, 130.1, 128.3, 125.4, 52.6, 36.9, 36.8, 36.8, 36.8, 33.1,32.5, 31.3, 30.7, 30.6, 30.5, 30.3, 30.3, 23.7, 14.5. HRMS: (ESI) [M+H]+calc. for C₂₃H₃₆N₃O, 370.2853, observed, 370.2859.

3-(3-(4-decylphenyl)-1,2,4-oxadiazol-5-yl)propan-1-amine2,2,2-trifluoroacetate (5e)

Synthesized according to General Procedure 5. Purified by silicachromatography (10% MeOH in DCM). White solid, 160 mg (63%) yield. ¹HNMR (400 MHz, CD₃OD) δ 7.93 (d, J=8.1 Hz, 2H), 7.29 (d, J=8.1 Hz, 2),3.19-3.07 (m, 4H), 2.64 (t, J=7.6 Hz, 2H), 2.25 (p, J=7.5 Hz, 2H),1.69-1.58 (m, 2H), 1.37-1.20 (m, 14H), 0.87 (t, J=6.6 Hz, 3H). ¹³C NMR(100 MHz, CD₃OD) δ 180.1, 169.4, 147.9, 130.0, 128.3, 125.3, 39.8, 36.8,33.0, 32.4, 30.7, 30.6, 30.4, 30.3, 25.1, 24.3, 23.7, 14.5. HRMS: (ESI)[M+H]+ calc. for C₂₁H₃₄N₃O, 344.2696, observed, 344.2701.

(3-(4-decylphenyl)-1,2,4-oxadiazol-5-yl)methanamine2,2,2-trifluoroacetate (5f)

Synthesized according to General Procedure 5. Purified by silicachromatography (10% MeOH in DCM). White solid, 250 mg (86%) yield. ¹HNMR (400 MHz, CD₃OD) δ 7.99 (d, J=7.8 Hz, 2H), 7.31 (d, J=7.8 Hz, 2H),4.60 (brs, 2H), 2.66 (t, J=7.7 Hz, 2H), 1.70-1.57 (m, 2H), 1.39-1.20 (m,14H), 0.88 (t, J=6.8 Hz, 3H). ¹³C NMR (100 MHz, CD₃OD) δ 174.4, 169.7,148.4, 130.1, 128.5, 124.7, 36.9, 36.1, 33.0, 32.4, 30.7, 30.6, 30.4,30.3, 23.7, 14.5. HRMS: (ESI) [M+H]+ calc. for C₁₉H₃₀N₃O, 316.2383,observed, 316.2393.

1-amino-3-(3-(4-decylphenyl)-1,2,4-oxadiazol-5-yl)propan-2-olhydrochloride (5g)

Synthesized according to General Procedure 6. White solid, 298 mg (87%)yield. ¹H NMR (400 MHz, CD₃OD) δ 7.95 (d, J=8.3 Hz, 2H), 7.33 (d, J=8.3Hz, 2H), 4.43-4.34 (m, 1H), 3.30=3.15 (m, 3H), 3.09-3.01 (m, 1H), 2.67(t, J=7.7 Hz, 2H), 1.70-1.60 (m, 2H), 1.38-1.21 (m, 14H), 0.88 (t, J=6.9Hz, 3H). ¹³C NMR (100 MHz, CD₃OD) δ 178.2, 169.6, 148.1, 130.1, 128.3,125.4, 66.5, 45.2, 36.9, 33.3, 33.1, 32.5, 30.7, 30.6, 30.5, 30.3, 23.7,14.5.

3-(4-decylphenyl)-5-(piperazin-1-ylmethyl)-1,2,4-oxadiazole2,2,2-trifluoroacetate (5h)

Synthesized according to General Procedure 6. White solid (49%, 100 mg).¹H NMR (400 MHz, CD₃OD) δ 7.91 (d, J=8.0 Hz, 2H), 7.27 (d, J=8.0 Hz,2H), 4.03 (s, 2H), 4.03-3.16 (m, 4H), 2.96-2.82 (m, 4H), 2.61 (t J=7.7Hz, 2H), 1.63-1.53 (m, 2H), 1.42-1.45 (m, 14H), 0.84 (t, J=6.7 Hz, 3H).¹³C NMR (101 MHz, CD₃OD) δ 177.2 169.5, 148.1, 130.1, 128.4, 125.2,122.9, 53.0, 50.2, 44.8, 36.8, 33.1, 32.4, 30.7, 30.6, 30.5, 30.3, 23.7,14.5. HRMS: (ESI) [M+H]+ calc. for C₂₃H₃₇N₄O, 385.2962, observed,385.2980.

3-(3-(4-(benzyloxy)phenyl)-1,2,4-oxadiazol-5-yl)propan-1-aminehydrochloride (5i)

Synthesized according to General Procedure 6. White solid (89%, 120 mg).¹H NMR (400 MHz, CDCl₃) δ 7.98 (d, J=9.0 Hz, 2H), 7.55-7.27 (m, 5H),7.13 (d, J=9.1 Hz, 2H), 5.16 (s, 2H), 3.19-3.06 (m, 4H), 2.23 (p, J=7.7Hz, 2H). ¹³C NMR (101 MHz, CDCl₃) δ 180.0, 169.2, 162.8, 138.2, 129.9,129.6, 129.1, 128.6, 120.4, 116.4, 71.1, 39.9, 25.2, 24.3. HRMS: (ESI)[M+H]+ calc. for C₁₈H₂₀N₃O₂, 310.1550, observed, 310.1530.

3-(3-(3-decylphenyl)-1,2,4-oxadiazol-5-yl)propan-1-amine hydrochloride(5j)

Synthesized according to General Procedure 6. White solid (53%, 90 mg).¹H NMR (400 MHz, CD₃OD) δ 7.87-7.81 (m, 2H), 7.38 (t, J=7.6 Hz, 1H),7.32 (d, J=7.6 Hz, 1H), 3.21-3.09 (m, 4H), 2.64 (t, J=7.7 Hz, 2H), 2.27(p, J=7.5 Hz, 2H), 1.62 (p, J=7.2 Hz, 2H), 1.39-1.17 (m, 14H), 0.87 (t,J=6.7 Hz, 3H). ¹³C NMR (101 MHz, CD₃OD) δ 180.2, 169.5, 144.9, 132.5,129.9, 128.1, 127.8, 125.7, 39.8, 36.7, 33.0, 32.6, 30.7, 30.6, 30.4,30.3, 28.8, 25.1, 24.3, 23.7, 14.5. HRMS: (ESI) [M+H]+ calc. forC₂₁H₃₄N₃O, 344.2696, observed, 344.2685.

(±)-3-chloro-3-(3-(4-decylphenyl)-1,2,4-oxadiazol-5-yl)propan-1-aminehydrochloride (5k)

Synthesized according to General Procedure 6. White solid (58%, 54 mg).¹H NMR (400 MHz, CDCl₃) δ 7.96 (d, J=8.2 Hz, 2H), 7.34 (d, J=8.2 Hz,2H), 4.84-4.76 (m, 1H), 3.72-3.55 (m, 3H), 3.44 (dd, J=13.7, 9.9 Hz,1H), 2.69 (t, J=7.7 Hz, 2H), 1.66 (p, J=7.7 Hz, 2H), 1.43-1.18 (m, 14H),0.89 (t, J=6.5 Hz, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 176.9, 169.7, 148.2,130.1, 128.3, 125.2, 55.6, 46.0, 36.8, 33.9, 33.1, 32.4, 30.7, 30.5,30.4, 30.3, 23.7, 14.4. HRMS: (ESI) [M+H]+ calc. for C₂₁H₃₃ClN₃O,378.2312, observed, 378.2312.

3-(3-(4-decylphenyl)-1,2,4-oxadiazol-5-yl)-N,N-dimethylpropan-1-aminehydrochloride (51)

Amine free base of the title compound was prepared according to GeneralProcedure 4. The title compound was prepared by dissolving the aminefree base in methanolic HCl followed by concentration in vacuo. Whitesolid (33%, 80 mg). ¹H NMR (400 MHz, CDCl₃) δ 7.96 (d, J=8.2 Hz, 2H),7.34 (d, J=7.34 (d, J=8.2 Hz, 2H), 3.40-3.30 (m, 2H), 3.14 (t, J=7.3 Hz,2H), 2.97 (s, 6H), 2.69 (t, J=7.7 Hz 2H), 2.40-2.29 (m, 2H), 1.66 (p,J=7.2 Hz, 2H), 1.42-1.22 (m, 14H), 0.90 (t, J=6.8 Hz, 3H). ¹³C NMR (101MHz, CDCl₃) δ 179.9, 169.5, 148.0, 130.1, 128.3, 125.3, 57.8, 43.6,36.8, 33.0, 32.4, 30.7, 30.5, 30.4, 30.3, 24.2, 23.7, 22.4, 14.4. HRMS:(ESI) [M+H]+ calc. for C₂₃H₃₈N₃O, 372.3009, observed, 372.3005.

3-(3-(4-decylphenyl)-1,2,4-oxadiazol-5-yl)-N-methylpropan-1-aminehydrochloride (5m)

Synthesized according to General Procedure 6. White solid (79%, 211 mg).¹H NMR (400 MHz, CDCl₃) δ 7.95 (d, J=7.8 Hz, 2H), 7.34 (d, J=7.7 Hz,2H), 3.20 (t, J=7.6 Hz, 2H), 3.13 (t, J=7.1 hz, 2H), 2.75 (s, 3H), 2.68(t, J=7.6 Hz, 2H), 2.35-2.20 (m, 2H), 1.71-1.59 (m, 2H), 1.42-1.20 (m,14H), 0.89 (t, J=6.4 Hz, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 179.9, 169.4,147.9, 130.0, 128.3, 125.3, 49.7, 36.8, 34.4, 33.0, 32.4, 30.6, 30.5,30.3, 30.2, 24.6, 24.0, 23.6, 14.4. HRMS: (ESI) [M+H]+ calc. forC₂₂H₃₆N₃O, 358.2853, observed, 358.2850.

1-amino-3-(3-(4-decylphenyl)-1,2,4-oxadiazol-5-yl)propan-2-yl acetatehydrochloride (5n)

Synthesized according to General Procedure 6. White solid (71%, 93 mg).¹H NMR (400 MHz, CDCl₃) δ 7.96 (d, J=7.8 Hz, 2H), 7.35 (d, J=7.9 Hz,2H), 5.57 (q, J=7.5, 7.1 Hz, 1H), 3.59-3.35 (m, 4H), 2.69 (t, J=7.6 Hz,2H), 2.12 (s, 3H), 1.66 (q, J=7.5 Hz, 2H), 1.32 (d, J=22.8 Hz, 14H),0.90 (t, J=6.6 Hz, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 176.9, 171.9, 169.6,148.2, 130.1, 128.3, 125.2, 68.8, 43.1, 36.8, 33.1, 32.4, 30.7, 30.5,30.4, 30.3, 30.0, 23.7, 20.8, 14.4 HRMS: (ESI) [M+H]+ calc. forC₂₃H₃₆N₃O₃, 402.2751, observed, 402.2747.

(3-(3-(4-decylphenyl)-1,2,4-oxadiazol-5-yl)phenyl)methanaminehydrochloride (5o)

Synthesized according to General Procedure 6. White solid (91%, 174 mg).¹H NMR (400 MHz, CD₃OD) δ 8.37 (s, 1H), 8.29 (dt, J=7.7, 1.5 Hz, 1H),8.05 (d, J=8.2 Hz, 2H), 7.79 (dt, J=7.8, 1.6 Hz, 1H), 7.73 (t, J=7.7 Hz,1H), 7.38 (d, J=8.3 Hz, 2H), 4.28 (s, 2H), 2.71 (t, J=7.5 Hz, 2H), 1.66(p, J=7.2 Hz, 2H), 1.44-1.21 (m, 14H), 0.88 (t, J=6.8 Hz, 3H). ¹³C NMR(101 MHz, CD₃OD) δ 174.6, 167.0, 148.9, 136.4, 134.6, 131.4, 130.2,129.7, 129.6, 128.4, 126.3, 125.4, 43.9, 36.9, 34.2, 32.4, 30.7, 30.6,30.4, 30.3, 23.1, 14.0. HRMS: (ESI) [M+H]+ calc. for C₂₅H₃₄N₃O,392.2696, observed, 392.2698.

(f)-cis-3-(3-(4-decylphenyl)-1,2,4-oxadiazol-5-yl)cyclohexan-1-aminehydrochloride (5p)

Synthesized according to General Procedure 6. White solid (87%, 226 mg).¹H NMR (400 MHz, CD₃OD) δ 7.95 (d, J=8.2 Hz, 2H), 7.32 (d, J=8.2 Hz,2H), 3.71-3.52 (m, J=20.7, 10.2, 5.1 Hz, 2H), 2.67 (t, J=7.7 Hz, 2H),2.61-2.51 (m, 1H), 2.26-2.16 (m, 1H), 2.10-1.77 (m, 4H), 1.71-1.51 (m,4H), 1.40-1.20 (m, 14H), 0.88 (t, J=6.8 Hz, 3H). ¹³C NMR (101 MHz,CD₃OD) δ 182.4, 169.5, 148.0, 130.1, 128.3, 125.4, 48.0, 36.8, 33.3,33.1, 32.9, 32.4, 30.8, 30.7, 30.5, 30.4, 30.3, 28.5, 23.7, 21.3, 14.4.HRMS: (ESI) [M+H]+ calc. for C₂₄H₃₈N₃O, 384.3009, observed, 384.2967.

(±)-trans-3-(3-(4-decylphenyl)-1,2,4-oxadiazol-5-yl)cyclohexan-1-aminehydrochloride (5q)

Synthesized according to General Procedure 6. White solid (74%, 192 mg).¹H NMR (400 MHz, CD₃OD) δ 7.93 (d, J=8.3 Hz, 2H), 7.31 (d, J=8.3 Hz,2H), 3.39-3.32 (m, 1H), 3.29-3.19 (m, 1H), 2.66 (d, J=7.8 Hz, 2H),2.57-2.50 (m, 1H), 2.28-2.19 (m, 1H), 2.17-2.09 (m, 1H), 2.08-2.01 (m,1H), 1.77 (q, J=12.3 Hz, 1H), 1.70-1.41 (m, 5H), 1.39-1.21 (m, 14H),0.88 (d, J=6.8 Hz, 3H). ¹³C NMR (101 MHz, CD₃OD) δ 182.6, 169.5, 148.0,130.1, 128.3, 125.4, 50.5, 36.8, 35.9, 34.8, 33.0, 32.4, 31.0, 30.7,30.5, 30.4, 30.3, 30.1, 24.4, 23.7, 14.4. HRMS: (ESI) [M+H]+ calc. forC₂₄H₃₈N₃O, 384.3009, observed, 384.2970.

3-(3-(4-nonylbenzyl)-1,2,4-oxadiazol-5-yl)propan-1-amine hydrochloride(5r)

Synthesized according to General Procedure 6. White solid (45%, 50 mg).¹H NMR (400 MHz, CD₃OD) δ 7.19 (d, J=8.0 Hz, 2H), 7.12 (d, J=8.0 Hz,2H), 4.01 (s, 2H), 3.13-2.97 (m, 4H), 2.57 (d, J=7.8 Hz, 2H), 2.13 (p,J=7.5 Hz, 2H), 1.58 (d, J=7.5 Hz, 2H), 1.40-1.22 (m, 12H), 0.89 (t,J=6.8 Hz, 3H). ¹³C NMR (101 MHz, CD₃OD) δ 178.8, 169.5, 141.5, 132.7,128.4, 128.3, 38.4, 35.1, 31.6, 31.3, 31.0, 29.3, 29.2, 29.0, 28.9,23.6, 22.8, 22.3, 13.0. HRMS: (ESI) [M+H]+ calc. for C₂₁H₃₄N₃O,344.2696, observed, 344.2703.

3-(3-(4-octylphenethyl)-1,2,4-oxadiazol-5-yl)propan-1-aminehydrochloride (5s)

Synthesized according to General Procedure 6. White solid (46%, 49 mg).¹H NMR (400 MHz, CD₃OD) δ 7.13-7.06 (m, 4H), 3.07 (dt, J=14.5, 7.5 Hz,4H), 3.00 (s, 4H), 2.55 (d, J=7.7 Hz, 2H), 2.17 (p, J=7.5 Hz, 2H), 1.59(p, J=7.5, 6.6 Hz, 2H), 1.37-1.21 (m, 10H), 0.89 (t, J=6.8 Hz, 3H). ¹³CNMR (101 MHz, CD₃OD) δ 179.9, 171.1, 142.1, 138.8, 129.6, 129.2, 39.8,36.5, 33.5, 33.0, 32.8, 30.6, 30.4, 30.3, 28.7, 25.1, 24.2, 23.7, 14.4.HRMS: (ESI) [M+H]+ calc. for C₂₁H₃₄N₃O, 344.2696, observed, 344.2700.

3-(3-(4-(nonyloxy)phenyl)-1,2,4-oxadiazol-5-yl)propan-1-aminehydrochloride (5t)

Synthesized according to General Procedure 6. White solid (88%, 226 mg).¹H NMR (400 MHz, CD₃OD) δ 7.96 (d, J=9.0 Hz, 2H), 7.03 (d, J=9.0 Hz,2H), 4.04 (t, J=6.4 Hz, 2H), 3.17-3.08 (m, 4H), 2.29-2.17 (m, 2H),1.85-1.74 (m, 2H), 1.55-1.44 (m, 2H), 1.44-1.23 (m, 10H), 0.93-0.86 (m,3H). ¹³C NMR (101 MHz, CD₃OD) δ 180.0, 169.3, 163.2, 129.9, 120.0,115.9, 69.3, 39.9, 33.0, 30.7, 30.5, 30.4, 30.3, 27.1, 25.2, 24.3, 23.7,14.4. HRMS: (ESI) [M+H]+ calc. for C₂₀H₃₂N₃O₂, 346.2489, observed,346.2480.

3-(3-(4-(nonyloxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)propan-1-aminehydrochloride (5u)

Synthesized according to General Procedure 6. White solid (72%, 155 mg).¹H NMR (400 MHz, CD₃OD) δ 8.25-8.20 (m, 2H), 7.30 (d, J=9.2 Hz, 1H),4.17 (t, J=6.2 Hz, 2H), 3.22-3.11 (m, 4H), 2.26 (p, J=7.5 Hz, 2H),1.87-1.75 (m, 2H), 1.52 (p, J=7.0 Hz, 2H), 1.41-1.26 (m, 10H), 0.89 (d,J=6.8 Hz, 3H). ¹³C NMR (101 MHz, CD₃OD) δ 180.5, 168.4, 160.7 (q, J=1.6Hz), 133.8, 127.0 (q, J=5.5 Hz), 124.8 (q, J=271.8 Hz), 120.2 (q, J=31.3Hz), 119.8, 114.8, 70.3, 39.8, 33.0, 30.6, 30.3, 30.3, 30.0, 26.9, 25.1,24.3, 23.7, 14.4. HRMS: (ESI) [M+H]+ calc. for C₂₁H₃₁F₃N₃O₂, 414.2363,observed, 414.2355.

3-(3-(3-fluoro-4-(nonyloxy)phenyl)-1,2,4-oxadiazol-5-yl)propan-1-aminehydrochloride (5v)

Synthesized according to General Procedure 6. White solid (79%, 236 mg).¹H NMR (400 MHz, CD₃OD) δ 7.8 (dt, J=8.6, 1.5 Hz, 1H), 7.7 (dd, J=11.9,2.0 Hz, 1H), 7.2 (t, J=8.5 Hz, 1H), 4.1 (t, J=6.4 Hz, 2H), 3.1 (q, J=7.4Hz, 2H), 2.2 (p, J=7.4 Hz, 2H), 1.9-1.7 (m, 2H), 1.6-1.4 (m, 2H),1.4-1.2 (m, 10H), 0.9 (d, J=6.8 Hz, 3H). ¹³C NMR (101 MHz, CD₃OD) δ180.3, 168.6 (d, J=2.6 Hz), 153.7 (d, J=245.8 Hz), 151.2 (d, J=10.7 Hz),125.1 (d, J=3.7 Hz), 120.5 (d, J=7.4 Hz), 115.8, 115.7 (d, J=23.9 Hz),70.4, 39.9, 33.0, 30.6, 30.4, 30.4, 30.2, 27.0, 25.2, 24.3, 23.7, 14.4.HRMS: (ESI) [M+H]+ calc. for C₂₀H₃₁FN₃O₂, 364.2395, observed, 364.2387.

3-(3-(6-(heptyloxy)naphthalen-2-yl)-1,2,4-oxadiazol-5-yl)propan-1-aminehydrochloride (5w)

Synthesized according to General Procedure 6. White solid (85%, 166 mg).¹H NMR (400 MHz, CD₃OD) δ 8.50 (d, J=1.6 Hz, 1H), 8.03 (dd, J=8.6 Hz,1H), 7.88 (d, J=3.5 Hz, 1H), 7.86 (d, J=3.8 Hz, 1H), 7.29 (d, J=2.4 Hz,1H), 7.21 (dd, J=9.0 Hz, 2.5 Hz, 1H), 4.13 (t, J=6.4 Hz, 2H), 3.21-3.11(m, 4H), 2.27 (p, J=7.4 Hz, 2H), 1.91-1.81 (m, 2H), 1.58-1.49 (m, 2H),1.47-1.31 (m, 6H), 0.93 (t, J=6.8 Hz, 3H). HRMS: (ESI) [M+H]+ calc. forC₂₁H₃₁F₃N₃O₂, 414.2363, observed, 414.2355.

(R)-3-(6-(heptyloxy)naphthalen-2-yl)-5-(pyrrolidin-3-yl)-1,2,4-oxadiazolehydrochloride (5x)

Synthesized according to General Procedure 6. White solid (75%, 175 mg).¹H NMR (400 MHz, CDCl₃) δ 10.3 (brs, 1H), 8.52 (d, J=1.7 Hz, 1H), 8.04(dd, J=8.6, 1.7 Hz, 1H), 7.83 (d, J=9.0 Hz, 1H), 7.77 (d, J=8.6 Hz, 1H),7.18 (dd, J=8.9, 2.5 Hz, 1H), 7.12 (d, J=2.5 Hz, 1H), 4.07 (t, J=6.6 Hz,2H), 4.01-3.91 (m, 2H), 3.88-3.78 (m, 2H), 3.69-3.58 (m, 2H), 2.71-2.59(m, 1H), 2.55-2.43 (m, 1H), 1.90-1.79 (m, 2H), 1.55-1.44 (m, 2H),1.43-1.25 (m, 6H), 0.90 (t, J=6.8 Hz, 3H). ¹³C NMR (101 MHz, CDCl₃) δ180.0, 169.8, 160.1, 137.9, 131.2, 129.7, 128.7, 125.0, 122.6, 121.1,111.4, 107.7, 69.2, 49.5, 46.6, 36.7, 33.0, 30.4, 30.3, 30.2, 27.2,23.7, 14.4. HRMS: (ESI) [M+H]+ calc. for C₂₃H₃₀N₃O₂, 380.2333, observed,380.2331.

(R)-2-amino-4-(3-(4-decylphenyl)-1,2,4-oxadiazol-5-yl)butanoic acidhydrochloride (5y)

Synthesized according to general procedure 4 with the followingadaptation. The Boc-protected product was then subjected to GeneralProcedure 6. White solid (69%, 145 mg). ¹H NMR (400 MHz, CD₃OD) δ 7.90(d, J=8.2 Hz, 2H), 7.27 (d, J=8.1 Hz, 2H), 4.19 (t, J=6.6 Hz, 1H),3.24-3.11 (m, 2H), 2.61 (t J=7.7 Hz, 2H), 2.55-2.35 (m, 2H), 1.59 (p,J=7.2 Hz, 2H), 1.35-1.15 (m, 14H), 0.83 (t, J=6.7 Hz, 3H). ¹³C NMR (101MHz, CD₃OD) δ 179.7, 171.1, 169.5, 148.0, 130.1, 128.3, 125.3, 53.0,36.8, 33.1, 32.4, 30.7, 30.6, 30.4, 30.3, 28.1, 28.0, 23.7, 23.5, 14.5.HRMS: (ESI) [M+H]+ calc. for C₂₂H₃₄N₃O₃, 388.2595, observed, 388.2595.

1-(3-(4-decylphenyl)-1,2,4-oxadiazol-5-yl)-3-(piperidin-1-yl)propan-2-olhydrochloride (6a)

Synthesized according to General Procedure 7 from 5g. Purified by silicachromatography (10% methanol in dichloromethane). White solid (19%, 10mg). ¹H NMR (400 MHz, CD₃OD) δ 7.96 (d, J=8.3 Hz, 2H), 7.33 (d, J=8.2Hz, 2H), 4.68-4.59 (m, 1H), 3.64 (d, J=11.9 Hz, 1H), 3.56 (d, J=12.5 Hz,1H), 3.39 (dd, J=13.3, 3.0 Hz, 1H), 3.27-2.95 (m, 5H), 2.68 (t, J=7.7Hz, 2H), 2.02-1.47 (m, 8H), 1.40-1.19 (m, 14H), 0.88 (t, J=6.7 Hz, 3H).¹³C NMR (101 MHz, CD₃OD) δ 176.5, 168.2, 146.7, 128.7, 126.9, 123.9,62.5, 60.4, 54.8, 51.7, 35.4, 32.1, 31.6, 31.0, 29.3, 29.1, 29.0, 28.9,22.4, 22.4, 22.3, 21.2, 13.0. HRMS: (ESI) [M+H]+ calc. for C₂₆H₄₂N₃O₂,428.3272, observed, 428.3264.

1-(3-(4-decylphenyl)-1,2,4-oxadiazol-5-yl)-3-(pyrrolidin-1-yl)propan-2-olhydrochloride (6b)

Synthesized according to General Procedure 7 from 5g. Purified by silicachromatography (5-15% methanol in dichloromethane). White solid (40%, 30mg). ¹H NMR (400 MHz, CD₃OD) δ 7.96 (d, J=8.2 Hz, 2H), 7.34 (d, J=8.2Hz, 2H), 4.55-4.47 (m, 1H), 3.39-3.32 (m, 6H), 3.28-3.14 (m, 2H), 2.68(t, J=7.7 Hz, 2H), 2.11-2.03 (m, 4H), 1.65 (p, J=7.4 Hz, 2H), 1.40-1.22(m, 14H), 0.89 (t, J=6.8 Hz, 3H). ¹³C NMR (101 MHz, CD₃OD) δ 178.2,169.6, 148.1, 130.1, 128.3, 125.4, 65.8, 60.7, 55.5, 36.8, 33.6, 33.1,32.5, 30.7, 30.6, 30.5, 30.3, 24.0, 23.7, 14.4. HRMS: (ESI) [M+H]+ calc.for C₂₅H₄₀N₃O₂, 414.3115, observed, 414.3133.

1-(3-(4-decylphenyl)-1,2,4-oxadiazol-5-yl)-3-morpholinopropan-2-olhydrochloride (6c)

Synthesized according to General Procedure 7 from 5g. Purified by silicachromatography (5-10% methanol in dichloromethane). White solid (64%, 84mg). ¹H NMR (400 MHz, CD₃OD) δ 7.96 (d, J=8.3 Hz, 2H), 7.33 (d, J=8.2Hz, 2H), 4.73-4.65 (m, 1H), 4.11-3.98 (m, 2H), 3.93-3.76 (m, 2H),3.65-3.52 (m, 2H), 3.51-3.63 (m, 2H), 3.34-3.17 (m, 4H), 2.68 (t, J=7.7Hz, 2H), 1.64 (p, J=7.4 Hz, 2H), 1.39-1.21 (m, 14H), 0.89 (t, J=6.7 Hz,3H). ¹³C NMR (101 MHz, CD₃OD) δ ¹³C NMR (101 MHz, CD₃OD) δ 177.9, 169.6,148.06, 130.1, 128.3, 125.4, 64.7, 63.7, 62.2, 54.8, 52.3, 36.8, 33.5,33.1, 32.5, 30.7, 30.6, 30.5, 30.3, 23.7, 14.5. HRMS: (ESI) [M+H]+ calc.for C₂₅H₄₀N₃O₃, 430.3064, observed, 430.3061.

3-(4-decylphenyl)-5-(3-(pyrrolidin-1-yl)propyl)-1,2,4-oxadiazolehydrochloride (6d)

Synthesized according to General Procedure 7 from 5e. Purified by silicachromatography (5-10% methanol in dichloromethane). White solid (68%, 56mg). ¹H NMR (400 MHz, CD₃OD) δ 7.95 (d, J=8.2 Hz, 2H), 7.33 (d, J=8.2Hz, 2H), 3.40-3.29 (m, 6H), 3.13 (t, J=7.3 Hz, 2H), 2.68 (t, J=7.7 Hz,2H), 2.37-2.27 (m, 2H), 2.14-2.04 (m, 4H), 1.65 (p, J=7.3 Hz, 2H),1.40-1.21 (m, 14H), 0.89 (t, J=6.8 Hz, 3H). ¹³C NMR (101 MHz, CD₃OD) δ180.1, 169.5, 148.1, 130.1, 128.3, 125.4, 55.3, 55.1, 36.8, 33.1, 32.5,30.7, 30.6, 30.5, 30.3, 24.4, 24.0, 24.0, 23.7, 14.5. HRMS: (ESI) [M+H]+calc. for C₂₅H₄₀N₃O, 398.3166, observed, 398.3155.

3-(4-decylphenyl)-5-(3-(piperidin-1-yl)propyl)-1,2,4-oxadiazolehydrochloride (6e)

Synthesized according to General Procedure 7 from 5e. Purified by silicachromatography (5-10% methanol in dichloromethane). White solid (38%, 32mg). ¹H NMR (400 MHz, CD₃OD) δ 7.94 (d, J=8.3 Hz, 2H), 7.31 (d, J=8.2Hz, 2H), 3.05 (t, J=7.3 Hz, 2H), 2.94-2.75 (m, 6H), 2.66 (t, J=7.7 Hz,2H), 2.20 (p, J=7.5 Hz, 2H), 1.72 (p, J=5.7 Hz, 2H), 1.69-1.51 (m, 4H),1.39-1.18 (m, 14H), 0.89 (t, J=6.7 Hz, 3H). ¹³C NMR (101 MHz, CD₃OD) δ180.7, 169.4, 147.9, 130.1, 128.3, 125.5, 58.2, 55.0, 36.9, 33.1, 32.5,30.7, 30.6, 30.5, 30.3, 25.5, 24.9, 24.0, 23.8, 23.2, 14.5. HRMS: (ESI)[M+H]+ calc. for C₂₆H₄₂N₃O, 412.3322, observed, 412.3315.

4-(3-(3-(4-decylphenyl)-1,2,4-oxadiazol-5-yl)propyl)morpholinehydrochloride (6f)

Synthesized according to General Procedure 7 from 5e. Purified by silicachromatography (5-10% methanol in dichloromethane). White solid (73%, 62mg). ¹H NMR (400 MHz, CD₃OD) δ 7.95 (d, J=8.2 Hz, 2H), 7.33 (d, J=8.1Hz, 2H), 4.13-3.76 (m, 4H), 3.63-3.48 (m, 2H), 3.41-3.33 (m, 2H),3.27-3.17 (m, 2H), 3.14 (t, J=7.3 Hz, 2H), 2.68 (t, J=7.7 Hz, 2H),2.43-2.32 (m, 2H), 1.65 (p, J=7.2 Hz, 2H), 1.39-1.21 (m, 14H), 0.89 (t,J=6.8 Hz, 3H). ¹³C NMR (101 MHz, CD₃OD) δ 179.9, 169.5, 148.1, 130.1,128.3, 125.4, 65.1, 57.3, 63.3, 36.8, 33.1, 32.5, 30.7, 30.6, 30.5,30.3, 24.3, 23.7, 21.6, 14.5. HRMS: (ESI) [M+H]+ calc. for C₂₅H₄₀N₃O₂,414.3115, observed, 414.3113.

1-(3-(4-decylphenyl)-1,2,4-oxadiazol-5-yl)-3-(ethylamino)propan-2-olhydrochloride (7a)

To a round bottom flask containing amine salt 5g was added methanol (0.1M), glacial acetic acid (2 equiv), and sodium cyanoborohydride at rt.Acetaldehyde (1.2 equiv) was then added and the mixture stirredovernight (ca. 16 hours) at rt. The reaction mixture was diluted indichloromethane and washed with 2M sodium bicarbonate solution andbrine. The aqueous layer was washed with dichloromethane 3×. Thecombined organic layers were dried over sodium sulfate and concentrated.Purified by silica chromatography (10% methanol in dichloromethane). Theproduct was then dissolved in methanolic HCl and concentrated to affordthe title compound as an HCl salt. White solid (27%, 20 mg). ¹H NMR (400MHz, CD₃OD) δ 7.96 (d, J=7.9 Hz, 2H), 7.34 (d, J=7.9 Hz, 2H), 4.54-4.41(m, 1H), 3.39-3.06 (m, 5H), 2.68 (t, J=7.8 Hz, 2H), 1.65 (p, J=7.2 Hz,2H), 1.41-1.20 (m, 17H), 0.89 (t, J=6.8 Hz, 3H). ¹³C NMR (101 MHz,CD₃OD) δ 178.1, 169.6, 148.1, 130.1, 128.3, 125.4, 65.7, 52.5, 44.1,36.8, 33.4, 33.1, 32.5, 30.7, 30.6, 30.5, 30.3, 23.7, 14.5, 11.4. HRMS:(ESI) [M+H]+ calc. for C₂₃H₃₈N₃O₂, 388.2959, observed, 388.2977.

1-(3-(4-decylphenyl)-1,2,4-oxadiazol-5-yl)-3-(dimethylamino)propan-2-olhydrochloride (7b)

To a round bottom flask was added amine salt 5g (1 equiv) followed byparaformaldehyde (10 equiv) and methanol (0.2M). Sodium borohydride (6equiv) was then added and the mixture was heated to reflux overnight(ca. 16 hours). The reaction mixture was diluted in dichloromethane andwashed with 2M sodium bicarbonate solution and brine. The aqueous layerwas washed with dichloromethane 3x. The combined organic layers weredried over sodium sulfate and concentrated. Purified by silicachromatography (0-15% methanol in dichloromethane). The product was thendissolved in methanolic HCl and concentrated to afford the titlecompound as an HCl salt. White solid (20%, 16 mg). ¹H NMR (400 MHz,CD₃OD) δ 7.96 (d, J=8.3 Hz, 2H), 7.34 (d, J=8.2 Hz, 2H), 4.53-4.44 (m,1H), 3.22 (dd, J=15.4, 5.0 Hz, 1H), 3.14 (dd, J=15.4, 7.0 Hz, 1H),3.09-3.04 (m, 2H), 2.73 (s, 6H), 2.68 (t, J=7.7 Hz, 2H), 1.65 (p, J=7.6hz, 2H), 1.39-1.22 (m, 14H), 0.89 (t, J=6.8 Hz, 3H). ¹³C NMR (101 MHz,CD₃OD) δ 178.4, 169.6, 148.0, 130.1, 128.3, 125.4, 65.4 63.7, 44.6,36.8, 33.6, 33.1, 32.5, 30.7, 30.6, 30.5, 30.3, 23.7, 14.4. HRMS: (ESI)[M+H]+ calc. for C₂₃H₃₈N₃O₂, 388.2959, observed, 388.2953.

tert-butyl(S)-(1-(((3-(4-decylphenyl)-1,2,4-oxadiazol-5-yl)methyl)amino)-1-oxopropan-2-yl)carbamate(8a)

Synthesized according to General Procedure 8. Purified via columnchromatography (35% ethyl acetate/hexanes). White solid (91%, 252 mg).¹H NMR (400 MHz, CDCl₃) δ 7.91 (d, J=8.3 Hz, 2H), 7.55 (brs, 1H), 7.24(d, J=8.2 Hz, 2H), 5.39 (d, J=7.7 Hz, 1H), 4.72 (d, J=5.7 Hz, 2H), 4.34(brs, 1H), 2.62 (t, J=7.7 Hz, 2H), 1.61 (p, J=7.2 Hz, 2H), 1.44-1.37 (s,12H), 1.33-1.22 (m, 14H), 0.86 (t, J=6.8 Hz, 3H). ¹³C NMR (101 MHz,CDCl₃) δ 175.81, 173.50, 168.46, 155.84, 146.75, 128.96, 127.47, 123.81,80.39, 50.02, 36.04, 35.80, 31.98, 31.28, 29.69, 29.66, 29.56, 29.41,29.36, 28.38, 22.76, 18.30, 14.20.

tert-butyl(2-(((3-(4-decylphenyl)-1,2,4-oxadiazol-5-yl)methyl)amino)-2-oxoethyl)carbamate(8b)

Synthesized according to General Procedure 8. Purified by silicachromatography (35% ethyl acetate in hexanes). Yellow oil (99%, 268 mg).¹H NMR (400 MHz, Chloroform-d) δ 7.92 (d, J=8.3 Hz, 2H), 7.39 (s, 1H),7.26 (d, J=10.4 Hz, 2H), 5.51 (s, 1H), 4.76 (s, 2H), 3.93 (s, 2H), 2.64(t, J=7.7 Hz, 2H), 1.61 (p, J=7.1 Hz, 2H), 1.44 (s, 9H), 1.35-1.22 (m,14H), 0.88 (t, J=6.7 Hz, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 175.67, 170.31,168.52, 156.40, 146.87, 129.01, 127.50, 123.73, 80.62, 44.38, 36.06,35.76, 32.00, 31.30, 29.71, 29.69, 29.58, 29.43, 29.39, 28.39, 22.79,14.22.

tert-butyl4-(2-(((3-(4-decylphenyl)-1,2,4-oxadiazol-5-yl)methyl)amino)-2-oxoethyl)piperazine-1-carboxylate(8c)

Synthesized according to General Procedure 8. Purified via columnchromatography (80% ethyl acetate/hexanes). Clear oil (82%, 190 mg). ¹HNMR (400 MHz, CDCl₃) δ 7.93 (d, J=8.0 Hz, 2H), 7.87 (t, J=5.9 Hz, 1H),7.29 (d, J=7.8 Hz, 2H), 4.80 (d, J=5.9 Hz, 2H), 3.51 (t, J=5.0 Hz, 4H),3.14 (s, 2H), 2.66 (t, J=7.4 Hz, 2H), 2.58 (t, J=5.1 Hz, 4H), 1.63 (p,J=7.4 Hz, 2H), 1.47 (s, 9H), 1.38-1.20 (m, 14H), 0.88 (t, J=6.8 Hz, 3H).¹³C NMR (101 MHz, CDCl₃) δ 175.94, 170.47, 168.50, 154.71, 146.93,129.09, 127.43, 123.77, 80.07, 61.48, 53.38, 43.94, 36.07, 35.40, 32.00,31.29, 29.71, 29.66, 29.57, 29.42, 29.37, 28.51, 22.78, 14.22.

tert-butyl(4-(((3-(4-decylphenyl)-1,2,4-oxadiazol-5-yl)methyl)amino)-4-oxobutyl)carbamate(8d)

Synthesized according to General Procedure 8. Purified by silicachromatography (35-50% ethyl acetate in hexanes). Yellow oil (87%, 124mg). ¹H NMR (400 MHz, Methanol-d₄) δ 7.92 (d, J=8.0 Hz, 2H), 7.29 (d,J=8.0 Hz, 2H), 4.66 (s, 2H), 3.10 (t, J=6.9 Hz, 2H), 2.65 (t, J=7.7 Hz,2H), 2.32 (t, J=7.5 Hz, 2H), 1.80 (p, J=7.2 Hz, 2H), 1.62 (p, J=7.3 Hz,2H), 1.41 (s, 9H), 1.34-1.23 (m, 14H), 0.87 (t, J=6.7 Hz, 3H). ¹³C NMR(101 MHz, Methanol-d₄) δ 178.31, 176.05, 169.51, 158.51, 147.98, 130.06,128.34, 125.26, 79.92, 40.71, 36.85, 36.46, 33.95, 33.07, 32.43, 30.71,30.70, 30.57, 30.46, 30.31, 28.78, 27.08, 23.74, 14.47.

tert-butyl(3-(((3-(4-decylphenyl)-1,2,4-oxadiazol-5-yl)methyl)amino)-3-oxopropyl)carbamate(8e)

Synthesized according to General Procedure 8. Purified via columnchromatography (35% ethyl acetate/hexanes). White solid (65%, 225 mg).¹H NMR (400 MHz, CDCl₃) δ 7.94 (d, J=8.2 Hz, 2H), 7.27 (d, J=7.9 Hz,2H), 6.95 (brs, 1H), 5.39 (brs, 1H), 4.73 (d, J=5.7 Hz, 2H), 3.46 (q,J=6.2 Hz, 2H), 2.65 (t, J=7.7 Hz, 2H), 2.53 (t, J=6.0 Hz, 2H), 1.63 (p,2H), 1.41 (s, 9H), 1.37-1.20 (m, 14H), 0.88 (t, J=6.7 Hz, 3H). ¹³C NMR(101 MHz, CDCl₃) δ 175.96, 172.09, 168.47, 156.36, 146.87, 129.04,127.51, 123.75, 79.61, 36.75, 36.43, 36.06, 35.88, 32.00, 31.30, 29.70,29.68, 29.58, 29.42, 29.37, 28.46, 22.78, 14.21.

tert-butyl(S)-(1-(((3-(4-decylphenyl)-1,2,4-oxadiazol-5-yl)methyl)amino)-3-methyl-1-oxobutan-2-yl)carbamate(8f)

Synthesized according to General Procedure 8. Purified via columnchromatography (30% ethyl acetate/hexanes). Yellow oil (80%, 47 mg). ¹HNMR (400 MHz, CDCl₃) δ 7.94 (d, J=8.4 Hz, 2H), 7.27 (d, J=7.9 Hz, 2H),7.00 (t, J=5.8 Hz, 1H), 5.18-5.04 (m, 1H), 4.75 (qd, J=17.4, 5.8 Hz,2H), 4.10-4.02 (m, 1H), 2.65 (t, J=7.8 Hz, 2H), 2.30-2.15 (m, 1H), 1.63(p, J=7.3 Hz, 2H), 1.44 (s, 9H), 1.34-1.22 (m, 14H), 1.02 (d, J=6.7 Hz,3H), 0.98 (d, J=6.8 Hz, 3H), 0.88 (t, J=6.8 Hz, 3H). ¹³C NMR (101 MHz,CDCl₃) δ 175.81, 172.50, 168.48, 156.19, 146.77, 129.00, 127.48, 123.88,80.21, 59.97, 36.07, 35.77, 32.01, 31.31, 31.08, 29.72, 29.69, 29.59,29.43, 29.39, 28.40, 22.79, 19.34, 18.10, 14.22. HRMS: (ESI) [M+H]+calc. for C₂₉H₄₇N₄O₄, 515.3592, observed, 515.3594.

tert-butyl(5-(((3-(4-decylphenyl)-1,2,4-oxadiazol-5-yl)methyl)amino)-5-oxopentyl)carbamate(8g)

Synthesized according to General Procedure 8. Purified via columnchromatography (40% ethyl acetate/hexanes). Yellow oil (96%, 141 mg). ¹HNMR (400 MHz, CDCl₃) δ 7.94 (d, J=8.1 Hz, 2H), 7.27 (d, J=8.1 Hz, 2H),6.72 (brs, 1H), 4.78-4.70 (m, 3H), 3.15 (q, J=6.7 Hz, 2H), 2.65 (t,J=7.6 Hz, 2H), 2.35 (t, J=7.4 Hz, 2H), 1.72 (p, J=7.2 Hz, 2H), 1.66-1.51(m, 4H), 1.41 (s, 9H), 1.36-1.22 (m, 14H), 0.88 (t, J=7.1 Hz, 3H). ¹³CNMR (101 MHz, CDCl₃) δ 176.07, 173.36, 168.48, 156.39, 146.85, 129.05,127.50, 123.85, 79.35, 39.76, 36.08, 35.89, 35.48, 32.01, 31.32, 29.72,29.69, 29.59, 29.48, 29.44, 29.39, 28.51, 22.80, 22.62, 14.23.

tert-butyl(2-((2-(3-(4-decylphenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)-2-oxoethyl)carbamate(8h)

Synthesized according to General Procedure 8. Purified via columnchromatography (35% ethyl acetate/dichloromethane). Clear oil (97%, 135mg). ¹H NMR (400 MHz, cd₃od) δ 7.94 (d, J=8.1 Hz, 2H), 7.30 (d, J=8.1Hz, 2H), 3.75-3.65 (m, 4H), 3.16 (t, J=6.6 Hz, 2H), 2.65 (t, J=7.7 Hz,2H), 1.63 (p, J=7.3 Hz, 2H), 1.38 (s, 9H), 1.29 (d, J=22.5 Hz, 14H),0.88 (t, J=6.7 Hz, 3H). ¹³C NMR (101 MHz, cd₃od) δ 179.42, 172.82,169.38, 158.32, 147.85, 130.04, 128.37, 125.44, 80.69, 44.66, 37.25,36.84, 33.07, 32.45, 30.73, 30.71, 30.59, 30.47, 30.30, 28.64, 27.55,23.74, 14.48.

tert-butyl(S)-2-(((3-(4-decylphenyl)-1,2,4-oxadiazol-5-yl)methyl)carbamoyl)piperidine-1-carboxylate(8i)

Synthesized according to General Procedure 8. Purified by silicachromatography (65% ethyl acetate in hexanes). Yellow oil (100%, 150mg). ¹H NMR (400 MHz, Chloroform-d) δ 7.95 (d, J=8.3 Hz, 2H), 7.27 (d,J=8.2 Hz, 2H), 7.04 (brs, 1H), 4.98-4.87 (m, 2H), 4.61 (brs, 1H), 4.11(brs, 1H), 2.95 (t, J=12.8 Hz, 1H), 2.65 (t, J=7.7 Hz, 3H), 2.34 (brs,1H), 1.70-1.55 (m, 6H), 1.49 (s, 9H), 1.37-1.19 (m, 14H), 0.88 (t, J=6.7Hz, 3H). ¹³C NMR (101 MHz, Chloroform-d) δ 175.97, 171.91, 168.47,146.84, 129.03, 127.49, 123.87, 81.00, 53.93, 42.44, 36.08, 35.93,32.01, 31.32, 29.72, 29.68, 29.59, 29.44, 29.39, 28.49, 25.45, 25.02,22.80, 20.60, 14.23.

tert-butyl(R)-3-(((3-(4-decylphenyl)-1,2,4-oxadiazol-5-yl)methyl)carbamoyl)pyrrolidine-1-carboxylate(8j)

Synthesized according to General Procedure 8. Purified via columnchromatography (35% ethyl acetate/hexanes). White solid (100%, 219 mg).¹H NMR (400 MHz, CDCl₃) δ 7.88 (d, J=8.0 Hz, 2H), 7.41-7.16 (m, 3H),4.81-4.55 (m, 2H), 3.71-3.40 (m, 3H), 3.29 (q, J=8.7 Hz, 1H), 3.00 (q,J=7.8 Hz, 1H), 2.60 (t, J=7.7 Hz, 2H), 2.20-2.04 (m, 2H), 1.57 (p, J=7.2Hz, 2H), 1.40 (s, 9H), 1.33-1.16 (m, 14H), 0.84 (t, J=6.7 Hz, 3H). ¹³CNMR (101 MHz, CDCl₃) δ 175.88, 172.95, 168.40, 154.45, 146.77, 128.95,127.37, 123.72, 79.57, 48.54, 45.54 (d, J=21.0 Hz), 43.91 (d, J=98.7Hz), 38.60, 35.97, 35.86, 31.92, 31.22, 29.63, 29.60, 29.50, 29.35,29.31, 28.49, 22.70, 14.14. HRMS: (ESI) [M+Na]+ calc. for C₂₉H₄₄N₄NaO₄,535.3255, observed, 535.3253.

tert-butyl(S)-3-(2-(((3-(4-decylphenyl)-1,2,4-oxadiazol-5-yl)methyl)amino)-2-oxoethyl)pyrrolidine-1-carboxylate(8k)

Synthesized according to General Procedure 8. Purified via columnchromatography (60% ethyl acetate/hexanes). Yellow oil (98%, 221 mg). ¹HNMR (400 MHz, CDCl₃) δ 7.92 (d, J=7.9 Hz, 2H), 7.25 (d, J=8.3 Hz, 2H),6.77 (dt, J=16.6, 10.7 Hz, 1H), 4.81-4.61 (m, 2H), 3.58 (q, J=9.4 Hz,1H), 3.49-3.36 (m, 1H), 3.28 (h, J=8.8 Hz, 1H), 2.96 (t, J=9.6 Hz, 1H),2.71-2.56 (m, 3H), 2.46-2.27 (m, 2H), 2.14-2.01 (m, 1H), 1.68-1.53 (m,3H), 1.42 (s, 9H), 1.35-1.20 (m, 14H), 0.86 (t, J=6.6 Hz, 3H).

tert-butyl(2-(((3-(4-decylphenyl)-1,2,4-oxadiazol-5-yl)methyl)amino)-2-oxoethyl)(methyl)carbamate(8l)

Synthesized according to General Procedure 8. Purified via columnchromatography (35% ethyl acetate/hexanes). White solid (86%, 83 mg). ¹HNMR (400 MHz, CDCl₃) δ 7.95 (d, J=8.3 Hz, 2H), 7.27 (d, J=8.3 Hz, 2H),6.89 (brs, 1H), 4.77 (d, J=5.7 Hz, 2H), 3.97 (s, 2H), 3.00 (s, 3H), 2.65(t, J=7.6 Hz, 2H), 1.63 (p, J=7.3 Hz, 2H), 1.48 (s, 9H), 1.38-1.21 (m,14H), 0.87 (t, J=6.8 Hz, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 175.60, 168.54,146.92, 129.06, 127.54, 123.80, 81.27, 53.27, 36.11, 36.01, 35.78,32.03, 31.35, 29.74, 29.71, 29.61, 29.46, 29.41, 28.45, 22.82, 14.26.HRMS: (ESI) [M+H]+ calc. for C₂₇H₄₃N₄O₄, 487.3279, observed, 487.3277.

tert-butyl(S)-2-(((3-(4-decylphenyl)-1,2,4-oxadiazol-5-yl)methyl)carbamoyl)pyrrolidine-1-carboxylate(8m)

Synthesized according to General Procedure 8. Purified by silicachromatography (35% ethyl acetate in hexanes). Yellow oil (95%, 278 mg).¹H NMR (400 MHz, Chloroform-d) δ 7.95 (d, J=8.2 Hz, 2H), 7.27 (d, J=8.2Hz, 2H), 4.87-4.60 (m, 2H), 4.41 (s, 1H), 3.43 (d, J=47.0 Hz, 2H),2.68-2.60 (m, 2H), 2.49-2.13 (m, 1H), 2.02-1.85 (m, 3H), 1.68-1.58 (m,2H), 1.47 (s, 9H), 1.38-1.20 (m, 14H), 0.90-0.85 (m, 3H). ¹³C NMR (101MHz, Chloroform-d) δ 175.95, 172.59, 168.49, 156.28, 146.76, 128.98,127.50, 123.88, 80.89, 60.72, 47.26, 36.06, 35.83, 31.99, 31.30, 29.70,29.67, 29.57, 29.50, 29.42, 29.36, 28.47, 24.44, 22.78, 14.21.

tert-butyl((2S,3S)-1-(((3-(4-decylphenyl)-1,2,4-oxadiazol-5-yl)methyl)amino)-3-methyl-1-oxopentan-2-yl)carbamate(8n)

Synthesized according to General Procedure 8. Purified via columnchromatography (30% ethyl acetate/hexanes). Yellow oil (92%, 138 mg). ¹HNMR (400 MHz, CDCl₃) δ 7.93 (d, J=8.2 Hz, 2H), 7.34-7.22 (m, 3H), 5.22(d, J=8.9 Hz, 1H), 4.89-4.61 (m, 2H), 4.12 (t, J=8.1 Hz, 1H), 2.64 (t,J=7.7 Hz, 2H), 1.98-1.89 (m, 1H), 1.69-1.54 (m, 3H), 1.42 (s, 9H),1.37-1.22 (m, 14H), 0.99 (d, J=6.8 Hz, 3H), 0.96-0.80 (m, 6H). ¹³C NMR(101 MHz, CDCl₃) δ 175.78, 172.46, 168.48, 156.12, 146.80, 129.01,127.51, 123.89, 80.27, 59.30, 37.31, 36.09, 35.80, 32.02, 31.33, 29.73,29.70, 29.60, 29.45, 29.40, 28.41, 24.88, 22.81, 15.64, 14.24, 11.49.

tert-butyl(S)-3-(2-(((3-(4-decylphenyl)-1,2,4-oxadiazol-5-yl)methyl)amino)-2-oxoethyl)piperidine-1-carboxylate(8o)

Synthesized according to General Procedure 8. Purified via columnchromatography (40% ethyl acetate/hexanes). Yellow oil (92%, 141 mg). ¹HNMR (400 MHz, CDCl₃) δ 7.94 (d, J=8.1 Hz, 2H), 7.45 (brs, 1H), 7.26 (d,J=8.1 Hz, 2H), 4.73 (d, J=5.7 Hz, 2H), 3.94-2.80 (m, 6H), 2.64 (t, J=7.7Hz, 2H), 2.40-2.26 (m, 1H), 2.16-2.08 (m, 2H), 1.96-1.82 (m, 1H),1.66-1.54 (m, 3H), 1.44 (s, 9H), 1.38-1.18 (m, 14H), 0.87 (t, J=6.8 Hz,3H). ¹³C NMR (101 MHz, CDCl₃) δ 176.10, 172.33, 168.48, 146.79, 129.02,127.51, 123.93, 79.87, 48.13, 45.09, 39.44, 36.08, 36.01, 33.22, 32.01,31.32, 30.75, 29.72, 29.69, 29.59, 29.44, 29.39, 28.54, 23.56, 22.80,14.23.

tert-butyl4-(((3-(4-decylphenyl)-1,2,4-oxadiazol-5-yl)methyl)carbamoyl)piperidine-1-carboxylate(8p)

Synthesized according to General Procedure 8. Purified via columnchromatography (60% ethyl acetate/hexanes). Clear oil (100%, 150 mg). ¹HNMR (400 MHz, CDCl₃) δ 7.95 (d, J=8.1 Hz, 2H), 7.28 (d, J=8.1 Hz, 2H),6.37 (t, J=5.6 Hz, 1H), 4.74 (d, J=5.5 Hz, 2H), 4.30-4.03 (m, 2H), 2.79(t, J=12.7 Hz, 2H), 2.65 (t, J=7.7 Hz, 2H), 2.39 (tt, J=11.4, 3.7 Hz,1H), 1.92-1.84 (m, 2H), 1.81-1.57 (m, 4H), 1.46 (s, 9H), 1.39-1.20 (m,14H), 0.88 (t, J=6.7 Hz, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 175.83, 174.68,168.50, 154.78, 146.96, 129.09, 127.52, 123.75, 79.84, 43.11, 36.10,35.96, 32.02, 31.33, 29.73, 29.70, 29.60, 29.45, 29.40, 29.39, 28.59,28.56, 22.81, 14.24.

tert-butyl(R)-2-(((3-(4-decylphenyl)-1,2,4-oxadiazol-5-yl)methyl)carbamoyl)morpholine-4-carboxylate(8q)

Synthesized according to General Procedure 8. Purified via columnchromatography (65% ethyl acetate/hexanes). Clear oil that turns towhite solid (40%, 60 mg). ¹H NMR (400 MHz, CDCl₃) δ 7.96 (d, J=8.2 Hz,2H), 7.29 (d, J=8.0 Hz, 3H), 4.78 (d, J=5.8 Hz, 2H), 4.36 (d, J=12.2 Hz,1H), 4.06-3.90 (m, 3H), 3.62 (td, J=11.7, 2.8 Hz, 1H), 2.89 (dt, J=40.4,12.0 Hz, 2H), 2.66 (t, J=7.7 Hz, 2H), 1.63 (p, J=7.8 Hz, 2H), 1.47 (s,9H), 1.38-1.20 (m, 14H), 0.88 (t, J=6.7 Hz, 3H). ¹³C NMR (101 MHz,CDCl₃) δ 175.37, 169.37, 168.63, 154.65, 146.93, 129.08, 127.56, 123.78,80.74, 75.06, 66.70, 46.13, 42.88, 36.10, 35.29, 32.02, 31.33, 29.73,29.70, 29.60, 29.45, 29.38, 28.49, 22.81, 14.25.

tert-butyl((1S,3R)-3-(((3-(4-decylphenyl)-1,2,4-oxadiazol-5-yl)methyl)carbamoyl)cyclohexyl)carbamate(8r)

Synthesized according to General Procedure 8. Purified via columnchromatography (35% ethyl acetate/hexanes). Yellow oil (93%, 143 mg). ¹HNMR (400 MHz, CDCl₃) δ 7.94 (d, J=8.0 Hz, 2H), 7.26 (d, J=8.1 Hz, 2H),6.78 (brs, 1H), 4.78-4.62 (m, 3H), 3.55-3.45 (m, 1H), 2.64 (t, J=15.5Hz, 2H), 2.35 (tt, J=10.2, 5.4 Hz, 1H), 2.24-2.14 (m, 1H), 2.00-1.91 (m,1H), 1.91-1.82 (m, 2H), 1.63 (p, J=7.3 Hz, 2H), 1.50-1.20 (m, 26H),1.16-1.04 (m, 1H), 0.87 (t, J=7.0 Hz, 3H). ¹³C NMR (101 MHz, CDCl₃) δ176.02, 175.34, 168.47, 155.35, 146.81, 129.01, 127.50, 123.83, 79.38,49.15, 44.12, 36.20, 36.06, 35.86, 32.75, 31.99, 31.30, 29.70, 29.67,29.57, 29.42, 29.38, 28.57, 28.52, 24.39, 22.78, 14.22. HRMS: (ESI)[M+H]+ calc. for C₃₁H₄₉N₄O₄, 541.3748, observed, 541.3743.

tert-butyl(S)-(1-(((3-(4-decylphenyl)-1,2,4-oxadiazol-5-yl)methyl)amino)-3-hydroxy-1-oxopropan-2-yl)carbamate(8s)

Synthesized according to General Procedure 8. Purified via columnchromatography (80-100% ethyl acetate/hexanes). Yellow oil (99%, 143mg). ¹H NMR (400 MHz, CDCl₃) δ 7.89 (d, J=7.8 Hz, 2H), 7.67 (t, J=6.0Hz, 1H), 7.26 (d, J=8.1 Hz, 2H), 5.73 (d, J=7.4 Hz, 1H), 4.83-4.65 (m,2H), 4.44-4.29 (m, 1H), 4.12 (dd, J=11.4, 3.4 Hz, 1H), 4.04-3.86 (m,1H), 3.82-3.66 (m, 1H), 2.64 (t, J=7.8 Hz, 2H), 1.62 (p, J=7.0 Hz, 2H),1.44 (s, 9H), 1.38-1.20 (m, 14H), 0.88 (t, J=6.7 Hz, 3H). ¹³C NMR (101MHz, CDCl₃) δ 176.26, 172.26, 168.20, 156.17, 147.03, 129.12, 127.45,123.46, 80.82, 63.26, 55.66, 36.08, 36.04, 32.02, 31.31, 29.73, 29.70,29.60, 29.45, 29.40, 28.41, 22.81, 14.25. HRMS: (ESI) [M+H]+ calc. forC₂₇H₄₃N₄O₅, 503.3228, observed, 503.3228.

tert-butyl(R)-2-(((3-(4-decylphenyl)-1,2,4-oxadiazol-5-yl)methyl)carbamoyl)piperidine-1-carboxylate(8t)

Synthesized according to General Procedure 8. Purified via columnchromatography (30% ethyl acetate/hexanes). Yellow oil (93%, 139 mg). ¹HNMR (400 MHz, CDCl₃) δ 7.95 (d, J=8.2 Hz, 2H), 7.27 (d, J=8.1 Hz, 2H),7.01 (brs, 1H), 4.97-4.79 (m, 2H), 4.70-4.51 (m, 1H), 4.22-3.99 (m, 1H),2.96 (t, J=12.9 Hz, 1H), 2.65 (t, J=7.7 Hz, 2H), 2.39-2.26 (m, 1H),1.72-1.53 (m, 7H), 1.49 (s, 9H), 1.36-1.21 (m, 14H), 0.88 (t, J=6.7 Hz,3H). ¹³C NMR (101 MHz, CDCl₃) δ 175.97, 171.91, 168.45, 146.82, 129.01,127.48, 123.87, 80.97, 53.77, 42.50, 36.07, 35.92, 32.00, 31.31, 29.71,29.67, 29.58, 29.43, 29.37, 28.47, 25.47, 25.01, 22.79, 20.59, 14.22.HRMS: (ESI) [M+Na]+ calc. for C₃₀H₄₆N₄NaO₄, 549.3411, observed,549.3411.

tert-butyl2-(((3-(4-decylphenyl)-1,2,4-oxadiazol-5-yl)methyl)carbamoyl)azepane-1-carboxylate(8u)

Synthesized according to General Procedure 8. Purified via columnchromatography (20% ethyl acetate/hexanes). Yellow oil (94%, 144 mg). ¹HNMR (400 MHz, CDCl₃) δ 7.94 (d, J=8.3 Hz, 2H), 7.34 (t, J=5.8 Hz, 1H),7.26 (d, J=8.2 Hz, 2H), 4.84-4.52 (m, 3H), 4.00-3.70 (m, 1H), 3.04-2.85(m, 1H), 2.64 (t, J=7.8 Hz, 2H), 2.40-2.09 (m, 1H), 2.00-1.56 (m, 7H),1.51-1.41 (m, 11H), 1.37-1.19 (m, 14H), 0.87 (t, J=6.8 Hz, 3H). ¹³C NMR(101 MHz, CDCl₃) δ 175.97, 172.85, 168.46, 157.20, 146.71, 128.97,127.50, 123.97, 80.68, 57.96, 43.91, 36.06, 35.74, 31.99, 31.30, 29.70,29.67, 29.57, 29.45, 29.42, 29.36, 28.89, 28.52, 28.49, 24.74, 22.77,14.21. HRMS: (ESI) [M+H]+ calc. for C₃₁H₄₉N₄O₄, 541.3748, observed,541.3735.

tert-butyl(2S,4S)-2-(((3-(4-decylphenyl)-1,2,4-oxadiazol-5-yl)methyl)carbamoyl)-4-hydroxypyrrolidine-1-carboxylate(8v)

Synthesized according to General Procedure 8. Purified via columnchromatography (80-100% ethyl acetate/hexanes). White solid (93%, 84mg). ¹H NMR (400 MHz, CDCl₃) δ 8.10 (brs, 1H), 7.94 (d, J=7.9 Hz, 2H),7.27 (d, J=7.8 Hz, 2H), 4.87-4.66 (m, 3H), 4.59-4.28 (m, 2H), 3.75-3.42(m, 2H), 2.65 (t, J=7.7 Hz, 2H), 2.44-2.14 (m, 2H), 1.62 (p, J=7.4 Hz,2H), 1.46 (s, 9H), 1.37-1.21 (m, 14H), 0.88 (t, J=6.7 Hz, 3H). ¹³C NMR(101 MHz, CDCl₃) δ 175.52, 174.17, 168.44, 155.82, 146.78, 128.98,127.49, 123.80, 81.09, 70.86, 59.43, 56.93, 38.68, 36.57, 36.04, 31.97,31.28, 29.68, 29.65, 29.56, 29.40, 29.35, 28.43, 22.76, 14.20. HRMS:(ESI) [M+H]+ calc. for C₂₉H₄₅N₄O₅, 529.3384, observed, 529.3374.

tert-butyl(2S,4R)-2-(((3-(4-decylphenyl)-1,2,4-oxadiazol-5-yl)methyl)carbamoyl)-4-hydroxypyrrolidine-1-carboxylate(8w)

Synthesized according to General Procedure 8. Purified via columnchromatography (80-100% ethyl acetate/hexanes). Yellow oil (96%, 144mg). ¹H NMR (400 MHz, CDCl₃) δ 7.92 (d, J=7.9 Hz, 2H), 7.26 (d, J=8.0Hz, 2H), 4.72 (d, J=5.8 Hz, 2H), 4.59-4.41 (m, 2H), 3.75-3.12 (m, 3H),2.64 (t, J=7.7 Hz, 2H), 2.54-2.08 (m, 2H), 1.62 (p, J=7.2 Hz, 2H), 1.44(s, 9H), 1.36-1.22 (m, 14H), 0.88 (t, J=6.7 Hz, 3H). ¹³C NMR (101 MHz,CDCl₃) δ 175.76, 172.45, 168.50, 156.23, 146.84, 129.00, 127.47, 123.76,81.20, 69.79, 58.52, 54.87, 38.71, 36.05, 35.76, 31.99, 31.29, 29.70,29.67, 29.57, 29.42, 29.38, 28.40, 22.77, 14.21. HRMS: (ESI) [M+H]+calc. for C₂₉H₄₅N₄O₅, 529.3384, observed, 529.3380.

tert-butyl(S)-3-(((3-(4-decylphenyl)-1,2,4-oxadiazol-5-yl)methyl)carbamoyl)pyrrolidine-1-carboxylate(8x)

Synthesized according to General Procedure 8. Purified via columnchromatography (35% ethyl acetate/hexanes). White solid (100%, 220 mg).¹H NMR (400 MHz, CDCl₃) δ 7.93 (d, J=8.0 Hz, 2H), 7.26 (d, J=8.0 Hz,2H), 7.07 (brs, 1H), 4.83-4.61 (m, 2H), 3.75-3.45 (m, 3H), 3.34 (q,J=8.5 Hz, 1H), 3.01 (q, J=7.3 Hz, 1H), 2.64 (t, J=7.7 Hz, 2H), 2.28-2.07(m, 2H), 1.62 (p, J=7.7 Hz, 2H), 1.44 (s, 9H), 1.37-1.21 (m, 14H), 0.88(t, J=6.7 Hz, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 175.84, 172.90, 168.46,154.47, 146.86, 129.01, 127.44, 123.74, 79.63, 48.60, 45.63 (d, J=13.6Hz), 44.06 (d, J=100.0 Hz), 38.67, 36.03, 35.94, 31.97, 31.27, 29.68,29.65, 29.55, 29.40, 29.35, 28.55, 22.75, 14.19. HRMS: (ESI) [M+Na]+calc. for C₂₉H₄₄N₄NaO₄, 535.3255, observed, 535.3247.

tert-butyl(R)-(4-(((3-(4-decylphenyl)-1,2,4-oxadiazol-5-yl)methyl)amino)-2-hydroxy-4-oxobutyl)carbamate(8y)

Synthesized according to General Procedure 8. Purified via columnchromatography (80% ethyl acetate/hexanes). White solid (94%, 32 mg). ¹HNMR (400 MHz, CDCl₃) δ 11.43 (s, 1H), 8.33 (t, J=5.4 Hz, 1H), 7.52 (d,J=1.8 Hz, 1H), 7.31-7.20 (m, 4H), 6.24 (d, J=1.8 Hz, 1H), 4.19 (t, J=7.1Hz, 2H), 3.38 (q, J=6.9 Hz, 2H), 2.63 (t, J=7.9 Hz, 2H), 2.11 (p, J=7.0Hz, 2H), 1.65 (p, J=7.6 Hz, 2H), 1.49 (s, 18H), 1.42-1.21 (m, 14H), 0.88(t, J=6.6 Hz, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 163.66, 156.27, 153.22,143.82, 143.61, 139.00, 128.88, 128.87, 128.02, 106.18, 83.13, 79.34,47.00, 38.30, 35.90, 32.05, 31.49, 29.87, 29.78, 29.73, 29.65, 29.55,29.48, 28.44, 28.21, 22.83, 14.26.

tert-butyl(S)-2-(((3-(4-decylphenyl)-1,2,4-oxadiazol-5-yl)methyl)carbamoyl)azetidine-1-carboxylate(8z)

Synthesized according to General Procedure 8. Purified via columnchromatography (70% ethyl acetate/hexanes). Yellow solid (100%, 142 mg).¹H NMR (400 MHz, CDCl₃) δ 8.48-7.80 (m, 3H), 7.27 (d, J=8.1 Hz, 2H),4.89-4.68 (m, 3H), 3.95 (q, J=8.3 Hz, 1H), 3.89-3.79 (m, 1H), 2.65 (t,J=7.7 Hz, 2H), 2.56-2.43 (m, 2H), 1.63 (q, J=7.5 Hz, 2H), 1.48 (s, 9H),1.36-1.22 (m, 14H), 0.88 (t, J=6.8 Hz, 3H). ¹³C NMR (101 MHz, CDCl₃) δ175.65, 172.12, 168.53, 157.57, 146.76, 128.97, 127.52, 123.87, 81.35,62.30, 47.41, 36.06, 35.71, 31.99, 31.32, 29.70, 29.67, 29.57, 29.42,29.37, 28.39, 22.78, 19.64, 14.23. HRMS: (ESI) [M+H]+ calc. forC₂₈H₄₃N₄O₄, 499.3279, observed, 499.3277.

tert-butyl(S)-5-((tert-butoxycarbonyl)amino)-6-(((3-(4-decylphenyl)-1,2,4-oxadiazol-5-yl)methyl)amino)-6-oxohexanoate(8aa)

Synthesized according to General Procedure 8. Purification via columnchromatography (30-40% ethyl acetate/hexanes). Yellow oil (30%, 67 mg).¹H NMR (400 MHz, CDCl₃) δ 7.95 (d, J=8.3 Hz, 2H), 7.36 (t, J=6.1 Hz,1H), 7.27 (d, J=8.0 Hz, 2H), 5.23 (d, J=7.8 Hz, 1H), 4.75 (d, J=5.6 Hz,2H), 4.23 (s, 1H), 2.65 (t, J=7.7 Hz, 2H), 2.34-2.22 (m, 2H), 1.80-1.56(m, 6H), 1.53-1.40 (m, 18H), 1.37-1.26 (m, 14H), 0.88 (t, J=6.8 Hz, 3H).¹³C NMR (101 MHz, CDCl₃) δ 175.71, 172.90, 172.54, 168.51, 156.04,146.81, 129.02, 127.54, 123.88, 80.63, 80.52, 54.20, 45.58, 36.09,35.89, 34.91, 32.02, 31.33, 29.73, 29.70, 29.60, 29.45, 29.40, 28.43,28.23, 22.81, 21.06, 14.24. HRMS: (ESI) [M+H]+ calc. for C₃₄H₅₅N₄O₆,615.4116, observed, 615.4113.

N-((3-(4-decylphenyl)-1,2,4-oxadiazol-5-yl)methyl)-2-(dimethylamino)acetamide(8ab)

Synthesized according to General Procedure 8. Purified via columnchromatography (100% ethyl acetate). White solid (88%, 77 mg). ¹H NMR(400 MHz, cd₃od) δ 7.93 (d, J=8.4 Hz, 2H), 7.31 (d, J=8.4 Hz, 2H), 4.72(s, 2H), 3.09 (s, 2H), 2.67 (t, J=7.7 Hz, 2H), 2.36 (s, 6H), 1.63 (p,J=7.4 Hz, 2H), 1.40-1.22 (m, 14H), 0.90 (t, J=6.9 Hz, 3H). ¹³C NMR (101MHz, cd₃od) δ 178.27, 173.81, 169.57, 148.05, 130.09, 128.32, 125.30,63.43, 46.02, 36.84, 36.26, 33.06, 32.42, 30.70, 30.69, 30.55, 30.44,30.30, 23.72, 14.44.

tert-butyl(S)-(1-(((3-(4-decylphenyl)-1,2,4-oxadiazol-5-yl)methyl)amino)-1-oxo-3-phenylpropan-2-yl)carbamate(8ac)

Synthesized according to General Procedure 8. Purified via columnchromatography (30% ethyl acetate). Yellow oil (98%, 157 mg). ¹H NMR(400 MHz, CDCl₃) δ 7.92 (d, J=8.1 Hz, 2H), 7.28-7.13 (m, 7H), 6.92 (brs,1H), 5.16 (d, J=7.9 Hz, 1H), 4.65 (d, J=5.7 Hz, 2H), 4.56-4.42 (m, 1H),3.15-3.03 (m, 2H), 2.63 (t, J=7.7 Hz, 2H), 1.62 (p, J=7.4 Hz, 2H),1.44-1.19 (m, 23H), 0.86 (t, J=6.8 Hz, 3H). ¹³C NMR (101 MHz, CDCl₃) δ175.44, 171.92, 168.48, 155.72, 146.86, 136.49, 129.41, 129.03, 128.81,127.53, 127.13, 123.80, 80.58, 55.81, 38.44, 36.09, 35.74, 32.02, 31.34,29.73, 29.70, 29.60, 29.45, 29.40, 28.37, 22.81, 14.25.

tert-butyl(S)-(1-(((3-(4-decylphenyl)-1,2,4-oxadiazol-5-yl)methyl)amino)-4-methyl-1-oxopentan-2-yl)carbamate(8ad)

Synthesized according to General Procedure 8. Purified via columnchromatography (30% ethyl acetate). Yellow oil (98%, 147 mg). ¹H NMR(400 MHz, CDCl₃) δ 7.94 (d, J=8.3 Hz, 2H), 7.33-7.22 (m, 3H), 5.06 (d,J=8.3 Hz, 1H), 4.82-4.66 (m, 2H), 4.26 (s, 1H), 2.65 (t, J=7.7 Hz, 2H),1.79-1.70 (m, 2H), 1.64 (p, J=7.7 Hz, 2H), 1.54 (dd, J=9.3, 8.0 Hz, 1H),1.43 (s, 9H), 1.38-1.19 (m, 14H), 0.96 (dd, J=7.5, 6.2 Hz, 6H), 0.88 (t,J=6.8 Hz, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 175.76, 173.24, 168.50,156.06, 146.82, 129.01, 127.53, 123.88, 80.55, 53.04, 41.01, 36.10,35.87, 32.02, 31.34, 29.73, 29.71, 29.60, 29.45, 29.41, 28.42, 24.84,23.04, 22.81, 22.12, 14.24.

tert-butyl(2S,4R)-2-(((3-(4-decylphenyl)-1,2,4-oxadiazol-5-yl)methyl)carbamoyl)-4-fluoropyrrolidine-1-carboxylate(8ae)

Synthesized according to General Procedure 8. Purified via columnchromatography (50% ethyl acetate). Yellow oil (95%, 143 mg). ¹H NMR(400 MHz, CDCl₃) δ 7.94 (d, J=8.0 Hz, 2H), 7.27 (d, J=8.1 Hz, 2H), 5.20(dt, J=52.9, 3.9 Hz, 1H), 4.74 (d, J=5.6 Hz, 2H), 4.68-4.39 (m, 1H),4.11-3.85 (m, 1H), 3.66-3.37 (m, 1H), 2.78-2.35 (m, 2H), 1.63 (p, J=7.1Hz, 2H), 1.53-1.39 (m, 9H), 1.38-1.20 (m, 14H), 0.87 (t, J=7.0 Hz, 1H).¹³C NMR (101 MHz, CDCl₃) δ 175.71, 171.61, 168.52, 156.04, 146.79,129.01, 127.51, 123.88, 91.91 (d, J=177.1 Hz), 81.56, 58.07, 53.57 (d,J=23.1 Hz), 36.07, 34.65 (d, J=20.6 Hz), 32.00, 31.31, 29.71, 29.68,29.58, 29.43, 29.38, 28.40, 22.79, 14.22.

(S)-2-amino-N-((3-(4-decylphenyl)-1,2,4-oxadiazol-5-yl)methyl)propanamidehydrochloride (9a)

Synthesized according to General Procedure 6. Purified via triturationwith ethyl acetate and diethyl ether. White solid (84%, 184 mg). ¹H NMR(400 MHz, cd₃od) δ 7.93 (d, J=8.3 Hz, 2H), 7.33 (d, J=8.2 Hz, 2H),4.83-4.70 (m, 2H), 4.07 (q, J=7.1 Hz, 1H), 2.68 (t, J=7.7 Hz, 2H), 1.66(p, J=7.4 Hz, 2H), 1.60 (d, J=7.1 Hz, 3H), 1.42-1.20 (m, 14H), 0.89 (t,J=6.8 Hz, 3H). ¹³C NMR (101 MHz, cd₃od) δ 177.82, 171.58, 169.62,148.17, 130.11, 128.31, 125.18, 50.23, 36.84, 36.55, 33.06, 32.43,30.69, 30.68, 30.55, 30.43, 30.30, 23.72, 17.47, 14.44. HRMS: (ESI)[M+H]+ calc. for C₂₂H₃₅N₄O₂, 387.2755, observed, 387.2764.

2-amino-N-((3-(4-decylphenyl)-1,2,4-oxadiazol-5-yl)methyl)acetamidehydrochloride (9b)

Synthesized according to General Procedure 6. White solid (69%, 159 mg).¹H NMR (400 MHz, Methanol-d₄) δ 7.94 (d, J=8.3 Hz, 2H), 7.34 (d, J=8.1Hz, 2H), 4.78 (s, 2H), 3.82 (s, 2H), 2.68 (t, J=7.7 Hz, 2H), 1.65 (p,J=7.3 Hz, 2H), 1.41-1.21 (m, 14H), 0.89 (t, J=6.6 Hz, 3H). ¹³C NMR (101MHz, Methanol-d₄) δ 177.87, 169.62, 167.97, 148.22, 130.13, 128.32,125.16, 41.49, 36.84, 36.46, 33.07, 32.46, 30.71, 30.69, 30.57, 30.45,30.31, 23.74, 14.44.

N-((3-(4-decylphenyl)-1,2,4-oxadiazol-5-yl)methyl)-2-(piperazin-1-yl)acetamidehydrochloride (9c)

Synthesized according to General Procedure 6. White solid (76%, 125 mg).¹H NMR (400 MHz, Methanol-d_(4) δ) 7.93 (d, J=8.2 Hz, 2H), 7.34 (d,J=8.2 Hz, 2H), 4.77 (s, 2H), 3.34-3.29 (m, 4H), 3.27 (s, 2H), 2.87 (t,J=7.8, 4H), 2.69 (t, J=7.7 Hz, 2H), 1.65 (p, J=7.3 Hz, 2H), 1.36-1.23(m, 14H), 0.90 (t, J=6.8 Hz, 3H). ¹³C NMR (101 MHz, Methanol-d₄) δ178.32, 172.97, 169.54, 148.10, 130.11, 128.28, 125.23, 61.61, 51.27,44.91, 36.83, 36.36, 33.04, 32.42, 30.68, 30.67, 30.54, 30.42, 30.29,23.71, 14.43. HRMS: (ESI) [M+H]+ calc. for C₂₅H₄₀N₅O₂, 442.3177,observed, 442.3171.

4-amino-N-((3-(4-decylphenyl)-1,2,4-oxadiazol-5-yl)methyl)butanamidehydrochloride (9d)

Synthesized according to General Procedure 6. White solid (76%, 108 mg).¹H NMR (400 MHz, Methanol-d₄) δ 7.93 (d, J=7.9 Hz, 2H), 7.31 (d, J=7.9Hz, 2H), 4.69 (s, 2H), 3.02 (t, J=7.5 Hz, 2H), 2.66 (t, J=7.7 Hz, 2H),2.50 (t, J=7.0 Hz, 2H), 1.99 (p, J=7.3 Hz, 2H), 1.64 (p, J=7.1 Hz, 2H),1.34-1.22 (m, 14H), 0.88 (t, J=6.6 Hz, 3H). ¹³C NMR (101 MHz, cd₃od) δ176.82, 173.60, 168.14, 146.63, 128.67, 126.90, 123.81, 38.88, 35.43,35.13, 31.86, 31.64, 31.01, 29.28, 29.15, 29.03, 28.90, 22.83, 22.31,13.05.

3-amino-N-((3-(4-decylphenyl)-1,2,4-oxadiazol-5-yl)methyl)propanamidehydrochloride (9e)

Synthesized according to General Procedure 6. Purified via triturationwith ethyl acetate. White solid (87%, 171 mg). ¹H NMR (400 MHz, cd₃od) δ7.95 (d, J=8.3 Hz, 2H), 7.34 (d, J=8.2 Hz, 2H), 4.74 (s, 2H), 3.25 (t,J=6.4 Hz, 2H), 2.77 (t, J=6.4 Hz, 2H), 2.69 (t, J=7.7 Hz, 2H), 1.66 (p,J=7.7 Hz, 2H), 1.40-1.24 (m, 14H), 0.90 (t, J=6.8 Hz, 3H). ¹³C NMR (101MHz, cd₃od) δ 178.19, 172.69, 169.58, 148.14, 130.11, 128.32, 125.19,36.87, 36.84, 36.38, 33.06, 32.59, 32.43, 30.70, 30.68, 30.55, 30.44,30.30, 23.72, 14.44. HRMS: (ESI) [M+H]+ calc. for C₂₂H₃₅N₄O₂, 387.2755,observed, 387.2763.

(S)-2-amino-N-((3-(4-decylphenyl)-1,2,4-oxadiazol-5-yl)methyl)-3-methylbutanamidehydrochloride (9f)

Synthesized according to General Procedure 6. Purified via triturationwith diethyl ether. White solid (83%, 34 mg). ¹H NMR (400 MHz, cd₃od) δ7.93 (d, J=8.3 Hz, 2H), 7.32 (d, J=8.6 Hz, 2H), 4.86-4.66 (m, 2H), 3.85(d, J=5.6 Hz, 1H), 2.67 (t, J=7.7 Hz, 2H), 2.37-2.24 (m, 1H), 1.65 (p,J=7.7 Hz, 2H), 1.40-1.24 (m, 14H), 1.20-1.10 (m, 6H), 0.89 (t, J=6.9 Hz,3H). ¹³C NMR (101 MHz, cd₃od) δ 177.78, 170.11, 169.57, 148.10, 130.08,128.29, 125.17, 59.70, 36.83, 36.49, 33.04, 32.40, 31.56, 30.68, 30.67,30.54, 30.42, 30.29, 23.71, 18.72, 18.00, 14.45. HRMS: (ESI) [M+H]+calc. for C₂₄H₃₉N₄O₂, 415.3068, observed, 415.3064.

5-amino-N-((3-(4-decylphenyl)-1,2,4-oxadiazol-5-yl)methyl)pentanamidehydrochloride (9g)

Synthesized according to General Procedure 6. Purification viatrituration with ethyl acetate. White solid (86%, 102 mg). ¹H NMR (400MHz, cd₃od) δ 7.95 (d, J=8.3 Hz, 2H), 7.34 (d, J=8.2 Hz, 2H), 4.70 (s,2H), 2.97 (t, J=6.8 Hz, 2H), 2.69 (t, J=7.7 Hz, 2H), 2.42 (t, J=6.6 Hz,2H), 1.80-1.62 (m, 6H), 1.42-1.23 (m, 14H), 0.90 (t, J=6.6 Hz, 3H). ¹³CNMR (101 MHz, cd₃od) δ 178.30, 175.86, 169.60, 148.12, 130.11, 128.31,125.26, 40.36, 36.84, 36.51, 35.52, 33.06, 32.44, 30.69, 30.68, 30.55,30.44, 30.30, 27.96, 23.72, 23.17, 14.43. HRMS: (ESI) [M+H]+ calc. forC₂₄H₃₉N₄O₂, 415.3068, observed, 415.3069.

2-amino-N-(2-(3-(4-decylphenyl)-1,2,4-oxadiazol-5-yl)ethyl)acetamidehydrochloride (9h)

Synthesized according to General Procedure 6. Purified via triturationwith ethyl acetate and diethyl ether. White solid (82%, 38 mg). ¹H NMR(400 MHz, cd₃od) δ 7.95 (d, J=8.3 Hz, 2H), 7.33 (d, J=8.1 Hz, 2H), 3.77(t, J=6.6 Hz, 2H), 3.67 (s, 2H), 3.23 (t, J=6.6 Hz, 2H), 2.67 (t, J=7.7Hz, 2H), 1.64 (p, J=7.3 Hz, 2H), 1.39-1.23 (m, 14H), 0.88 (t, J=7.0 Hz,3H). ¹³C NMR (101 MHz, cd₃od) δ 179.31, 169.49, 167.56, 147.99, 130.07,128.32, 125.39, 41.45, 37.63, 36.84, 33.06, 32.46, 30.71, 30.70, 30.57,30.45, 30.31, 27.55, 23.73, 14.45. HRMS: (ESI) [M+NH₄]+ calc. forC₂₂H₃₈N₅O₂, 404.3020, observed, 404.3029.

(S)—N-((3-(4-decylphenyl)-1,2,4-oxadiazol-5-yl)methyl)piperidine-2-carboxamidehydrochloride (9i)

Synthesized according to General Procedure 6. White solid (88%, 44 mg).¹H NMR (400 MHz, Methanol-d₄) δ 7.92 (d, J=8.2 Hz, 2H), 7.31 (d, J=8.1Hz, 2H), 4.83-4.68 (m, 2H), 3.98 (dd, J=11.6, 3.3 Hz, 1H), 3.40 (dt,J=13.3, 2.8 Hz, 1H), 3.07 (td, J=12.5, 3.6 Hz, 1H), 2.66 (t, J=7.7 Hz,2H), 2.32 (dt, J=12.8, 3.4 Hz, 1H), 2.01-1.57 (m, 7H), 1.39-1.20 (m,14H), 0.88 (t, J=6.7 Hz, 3H). ¹³C NMR (101 MHz, Methanol-d₄) δ 176.35,169.21, 168.20, 146.73, 128.69, 126.90, 123.76, 57.50, 43.58, 35.43,35.08, 31.64, 31.01, 29.28, 29.27, 29.14, 29.02, 28.89, 27.04, 22.31,21.55, 21.43, 13.04.

(R)—N-((3-(4-decylphenyl)-1,2,4-oxadiazol-5-yl)methyl)pyrrolidine-3-carboxamidehydrochloride (9j)

Synthesized according to General Procedure 6. Purified via triturationwith ethyl acetate and diethyl ether. White solid (69%, 132 mg). ¹H NMR(400 MHz, cd₃od) δ 7.92 (d, J=8.2 Hz, 2H), 7.32 (d, J=8.0 Hz, 2H),4.78-4.64 (m, 2H), 3.59-3.45 (m, 2H), 3.43-3.33 (m, 3H), 2.67 (t, J=7.7Hz, 2H), 2.47-2.34 (m, 1H), 2.30-2.18 (m, 1H), 1.64 (p, J=7.5 Hz, 2H),1.41-1.20 (m, 14H), 0.89 (t, J=6.7 Hz, 3H). ¹³C NMR (101 MHz, cd₃od) δ178.10, 174.69, 169.55, 148.08, 130.09, 128.30, 125.20, 48.63, 46.55,43.63, 36.83, 36.63, 33.04, 32.41, 30.68, 30.67, 30.54, 30.42, 30.29,30.20, 23.71, 14.44. HRMS: (ESI) [M+H]+ calc. for C₂₄H₃₇N₄O₂, 413.2911,observed, 413.2904.

(S)—N-((3-(4-decylphenyl)-1,2,4-oxadiazol-5-yl)methyl)-2-(pyrrolidin-3-yl)acetamidehydrochloride (9k)

Synthesized according to General Procedure 6. Purification viatrituration with ethyl acetate. White solid (94%, 182 mg). ¹H NMR (400MHz, cd₃od) δ 7.95 (d, J=8.3 Hz, 2H), 7.34 (d, J=8.3 Hz, 2H), 4.71 (s,2H), 3.55 (dd, J=11.7, 7.6 Hz, 1H), 3.49-3.37 (m, 1H), 3.31-3.22 (m,1H), 3.03 (dd, J=11.7, 8.9 Hz, 1H), 2.81-2.65 (m, 3H), 2.65-2.49 (m,2H), 2.35-2.23 (m, 1H), 1.85-1.75 (m, 1H), 1.66 (q, J=7.0 Hz, 2H),1.41-1.23 (m, 14H), 0.91 (t, J=6.8 Hz, 3H). ¹³C NMR (101 MHz, cd₃od) δ178.24, 174.07, 169.56, 148.06, 130.09, 128.29, 125.23, 50.90, 46.19,38.71, 36.83, 36.49, 36.22, 33.04, 32.41, 30.97, 30.68, 30.67, 30.54,30.42, 30.30, 23.71, 14.44. HRMS: (ESI) [M+H]+ calc. for C₂₅H₃₉N₄O₂,427.3068, observed, 427.3071.

N-((3-(4-decylphenyl)-1,2,4-oxadiazol-5-yl)methyl)-2-(methylamino)acetamidehydrochloride (9l)

Synthesized according to General Procedure 6. Purified via triturationwith ethyl acetate and diethyl ether. White solid (70%, 50 mg). ¹H NMR(400 MHz, cd₃od) δ 7.93 (d, J=8.3 Hz, 2H), 7.33 (d, J=8.2 Hz, 2H), 4.78(s, 2H), 3.96 (s, 2H), 2.77 (s, 3H), 2.67 (t, J=7.7 Hz, 2H), 1.64 (p,J=7.3 Hz, 2H), 1.40-1.28 (m, 14H), 0.89 (t, J=6.8 Hz, 3H). ¹³C NMR (101MHz, cd₃od) δ 177.76, 169.61, 167.17, 148.15, 130.10, 128.31, 125.15,50.52, 36.83, 36.42, 33.62, 33.05, 32.41, 30.68, 30.67, 30.54, 30.42,30.29, 23.71, 14.43. HRMS: (ESI) [M+H]+ calc. for C₂₂H₃₅N₄O₂, 387.2755,observed, 387.2738.

(S)—N-((3-(4-decylphenyl)-1,2,4-oxadiazol-5-yl)methyl)pyrrolidine-2-carboxamidehydrochloride (9m)

Synthesized according to General Procedure 6. White solid (94%, 160 mg).¹H NMR (400 MHz, Methanol-d₄) δ 7.93 (d, J=8.2 Hz, 2H), 7.32 (d, J=8.0Hz, 2H), 4.84-4.72 (m, 2H), 4.43 (dd, J=8.6, 6.6 Hz, 1H), 3.46-3.33 (m,2H), 2.67 (t, J=7.7 Hz, 2H), 2.57-2.47 (m, 1H), 2.21-2.03 (m, 3H), 1.64(p, J=7.1 Hz, 2H), 1.31 (d, J=24.5 Hz, 14H), 0.89 (t, J=6.8 Hz, 3H). ¹³CNMR (101 MHz, Methanol-d₄) δ 177.76, 170.37, 169.60, 148.16, 130.11,128.30, 125.15, 61.14, 47.39, 36.83, 36.72, 33.05, 32.42, 30.87, 30.70,30.68, 30.54, 30.43, 30.29, 24.98, 23.72, 14.43. HRMS: (ESI) [M+H]+calc. for C₂₄H₃₇N₄O₂, 413.2911, observed, 413.2909.

(2S,3S)-2-amino-N-((3-(4-decylphenyl)-1,2,4-oxadiazol-5-yl)methyl)-3-methylpentanamidehydrochloride (9n)

Synthesized according to General Procedure 6. Purified via triturationwith diethyl ether. White solid (87%, 105 mg). ¹H NMR (400 MHz, cd₃od) δ7.93 (d, J=8.0 Hz, 2H), 7.32 (d, J=8.0 Hz, 2H), 4.92-4.60 (m, 2H), 3.88(d, J=5.2 Hz, 1H), 2.68 (t, J=7.7 Hz, 2H), 2.07-1.96 (m, 1H), 1.74-1.59(m, 3H), 1.39-1.23 (m, 14H), 1.11 (d, J=6.9 Hz, 3H), 1.03 (t, J=7.4 Hz,3H), 0.89 (t, J=6.7 Hz, 3H). ¹³C NMR (101 MHz, cd₃od) δ 177.81, 170.05,169.59, 148.16, 130.10, 128.30, 125.18, 59.01, 38.13, 36.83, 36.50,33.05, 32.42, 30.68, 30.68, 30.54, 30.43, 30.29, 25.52, 23.72, 15.01,14.44, 11.83. HRMS: (ESI) [M+H]+ calc. for C₂₅H₄₁N₄O₂, 429.3224,observed, 429.3231.

(S)—N-((3-(4-decylphenyl)-1,2,4-oxadiazol-5-yl)methyl)-2-(piperidin-3-yl)acetamidehydrochloride (9o)

Synthesized according to General Procedure 6. Purified via triturationwith diethyl ether. White solid (81%, 100 mg). ¹H NMR (400 MHz, cd₃od) δ8.95 (t, J=5.8 Hz, 1H), 7.94 (d, J=8.0 Hz, 2H), 7.33 (d, J=8.0 Hz, 2H),4.70 (s, 2H), 3.52-3.35 (m, 2H), 2.94 (td, J=12.7, 3.2 Hz, 1H), 2.81 (t,J=11.9 Hz, 1H), 2.68 (t, J=7.7 Hz, 2H), 2.41-2.24 (m, 3H), 2.04-1.90 (m,2H), 1.88-1.73 (m, 1H), 1.65 (p, J=7.3 Hz, 2H), 1.45-1.22 (m, 15H), 0.90(t, J=6.7 Hz, 3H). ¹³C NMR (101 MHz, cd₃od) δ 178.21, 173.71, 169.52,148.02, 130.08, 128.28, 125.22, 49.35, 45.18, 40.17, 36.83, 36.53,33.03, 32.59, 32.40, 30.68, 30.66, 30.54, 30.42, 30.30, 29.33, 23.70,23.21, 14.45. HRMS: (ESI) [M+H]+ calc. for C₂₆H₄₁N₄O₂, 441.3224,observed, 441.3232.

N-((3-(4-decylphenyl)-1,2,4-oxadiazol-5-yl)methyl)piperidine-4-carboxamidehydrochloride (9p)

Synthesized according to General Procedure 6. via trituration with ethylacetate and diethyl ether. White solid (70%, 97 mg). H NMR (400 MHz,cd₃od) δ 7.93 (d, J=8.3 Hz, 2H), 7.33 (d, J=8.2 Hz, 2H), 4.69 (s, 2H),3.45 (dt, J=13.0, 4.0 Hz, 2H), 3.10 (td, J=12.7, 3.3 Hz, 2H), 2.78-2.64(m, 3H), 2.16-2.05 (m, 2H), 2.02-1.87 (m, 2H), 1.65 (p, J=7.5 Hz, 2H),1.41-1.22 (m, 14H), 0.89 (t, J=6.6 Hz, 3H). ¹³C NMR (101 MHz, cd₃od) δ178.21, 176.33, 169.57, 148.08, 130.09, 128.30, 125.25, 44.21, 40.41,36.83, 36.53, 33.05, 32.42, 30.69, 30.68, 30.55, 30.43, 30.29, 26.48,23.72, 14.43. HRMS: (ESI) [M+H]+ calc. for C₂₅H₃₉N₄O₂, 427.3068,observed, 427.3070.

(R)—N-((3-(4-decylphenyl)-1,2,4-oxadiazol-5-yl)methyl)morpholine-2-carboxamidehydrochloride (9q)

Synthesized according to General Procedure 6. Purified via triturationwith ethyl acetate and diethyl ether. White solid (69%, 36 mg). ¹H NMR(400 MHz, cd₃od) δ 7.95 (d, J=8.3 Hz, 2H), 7.34 (d, J=8.2 Hz, 2H), 4.73(s, 2H), 4.11 (dd, J=10.5, 2.9 Hz, 1H), 4.02 (dt, J=11.4, 2.5 Hz, 1H),3.79-3.66 (m, 1H), 3.24 (dd, J=12.7, 2.9 Hz, 1H), 2.91-2.82 (m, 2H),2.81-2.65 (m, 3H), 1.66 (p, J=7.2 Hz, 2H), 1.42-1.30 (m, 14H), 0.91 (t,J=6.7 Hz, 3H). ¹³C NMR (101 MHz, cd₃od) δ 177.97, 172.89, 169.57,148.03, 130.07, 128.34, 125.25, 76.79, 68.07, 48.65, 45.72, 36.84,36.05, 33.05, 32.42, 30.69, 30.69, 30.55, 30.43, 30.30, 23.72, 14.45.HRMS: (ESI) [M+H]+ calc. for C₂₄H₃₇N₄O₃, 429.2860, observed, 429.2865.

(1R,3S)-3-amino-N-((3-(4-decylphenyl)-1,2,4-oxadiazol-5-yl)methyl)cyclohexane-1-carboxamidehydrochloride (9r)

Synthesized according to General Procedure 6. Purification viatrituration with diethyl ether. White solid (86%, 108 mg). ¹H NMR (400MHz, cd₃od) δ 7.91 (d, J=8.2 Hz, 2H), 7.29 (d, J=8.1 Hz, 2H), 4.67 (s,2H), 3.21 (tt, J=11.7, 3.9 Hz, 1H), 2.64 (t, J=7.7 Hz, 2H), 2.52 (tt,J=11.8, 3.3 Hz, 1H), 2.22-2.13 (m, 1H), 2.11-2.01 (m, 1H), 1.99-1.87 (m,2H), 1.68-1.20 (m, 20H), 0.87 (t, J=6.9 Hz, 3H). ¹³C NMR (101 MHz,cd₃od) δ 176.80, 176.00, 168.14, 146.60, 128.67, 126.91, 123.87, 49.26,42.43, 35.45, 35.13, 32.54, 31.66, 31.03, 29.71, 29.31, 29.30, 29.17,29.05, 28.92, 28.01, 22.98, 22.33, 13.09. HRMS: (ESI) [M+H]+ calc. forC₂₆H₄₁N₄O₂, 441.3224, observed, 441.3217.

(S)-2-amino-N-((3-(4-decylphenyl)-1,2,4-oxadiazol-5-yl)methyl)-3-hydroxypropanamidehydrochloride (9s)

Synthesized according to General Procedure 6. Purified via triturationwith ethyl acetate. White solid (75%, 94 mg). ¹H NMR (400 MHz, cd₃od) δ7.95 (d, J=8.3 Hz, 2H), 7.35 (d, J=8.1 Hz, 2H), 4.85-4.73 (m, 2H), 4.10(dd, J=6.5, 4.2 Hz, 1H), 4.04 (dd, J=11.6, 4.2 Hz, 1H), 3.94 (dd,J=11.6, 6.4 Hz, 1H), 2.69 (t, J=7.7 Hz, 2H), 1.67 (p, J=7.5 Hz, 2H),1.42-1.23 (m, 14H), 0.91 (t, J=6.6 Hz, 3H). ¹³C NMR (101 MHz, cd₃od) δ177.85, 169.59, 168.92, 148.19, 130.12, 128.32, 125.15, 61.60, 56.34,36.83, 36.60, 33.05, 32.43, 30.69, 30.67, 30.55, 30.43, 30.29, 23.72,14.43. HRMS: (ESI) [M+H]+ calc. for C₂₂H₃₅N₄O₃, 403.2704, observed,403.2714.

(R)—N-((3-(4-decylphenyl)-1,2,4-oxadiazol-5-yl)methyl)piperidine-2-carboxamidehydrochloride (9t)

¹H NMR (400 MHz, CD₃OD) δ 7.93 (d, J=8.5 Hz, 2H), 7.33 (d, J=8.6 Hz,2H), 4.70 (d, J=1.2 Hz, 2H), 3.40-3.34 (m, 1H), 3.14-3.07 (m, 1H),2.73-2.64 (m, 3H), 2.02-1.94 (m, 1H), 1.91-1.84 (m, 1H), 1.70-1.58 (m,3H), 1.57-1.44 (m, 3H), 1.38-1.27 (m, 14H), 0.88 (t, J=6.8 Hz, 3H). ¹³CNMR (101 MHz, CD₃OD) δ 178.19, 175.96, 169.58, 148.09, 130.09, 128.32,125.28, 60.59, 46.27, 36.84, 36.34, 33.06, 32.43, 30.82, 30.71, 30.69,30.55, 30.44, 30.30, 26.38, 24.93, 23.73, 14.43. HRMS: (ESI) [M+H]+calc. for C₂₅H₃₉N₄O₂, 427.3068, observed, 427.3060.

N-((3-(4-decylphenyl)-1,2,4-oxadiazol-5-yl)methyl)azepane-2-carboxamidehydrochloride (9u)

Synthesized according to General Procedure 6. Purified via triturationwith diethyl ether. White solid (78%, 99 mg). ¹H NMR (400 MHz, cd₃od) δ7.93 (d, J=8.3 Hz, 2H), 7.33 (d, J=8.2 Hz, 2H), 4.84-4.70 (m, 2H), 4.15(dd, J=9.7, 3.5 Hz, 1H), 3.40-3.32 (m, 1H), 3.30-3.19 (m, 1H), 2.68 (t,J=7.7 Hz, 2H), 2.43-2.31 (m, 1H), 2.13-2.00 (m, 1H), 1.96-1.59 (m, 8H),1.40-1.24 (m, 14H), 0.89 (t, J=6.7 Hz, 3H). ¹³C NMR (101 MHz, cd₃od) δ177.79, 171.31, 169.62, 148.18, 130.12, 128.30, 125.17, 60.82, 46.84,36.83, 36.64, 33.05, 32.42, 31.07, 30.69, 30.68, 30.54, 30.43, 30.29,27.33, 26.40, 26.17, 23.72, 14.43. HRMS: (ESI) [M+H]+ calc. forC₂₆H₄₁N₄O₂, 441.3224, observed, 441.3229.

(2S,4S)—N-((3-(4-decylphenyl)-1,2,4-oxadiazol-5-yl)methyl)-4-hydroxypyrrolidine-2-carboxamidehydrochloride (9v)

Synthesized according to General Procedure 6. Purified via triturationwith diethyl ether and ethyl acetate. White solid (83%, 32 mg). ¹H NMR(400 MHz, cd₃od) δ 7.93 (d, J=8.3 Hz, 2H), 7.31 (d, J=8.2 Hz, 2H),4.82-4.77 (m, 2H), 4.61-4.48 (m, 2H), 3.40 (d, J=3.2 Hz, 2H), 2.76-2.64(m, 3H), 2.30-2.20 (m, 1H), 1.64 (p, J=7.4 Hz, 2H), 1.41-1.22 (m, 14H),0.89 (t, J=6.8 Hz, 3H). ¹³C NMR (101 MHz, cd₃od) δ 177.68, 170.45,169.58, 148.08, 130.07, 128.33, 125.15, 70.30, 59.97, 54.51, 39.28,36.83, 33.03, 32.40, 30.68, 30.66, 30.54, 30.42, 30.29, 23.70, 14.44.HRMS: (ESI) [M+H]+ calc. for C₂₄H₃₇N₄O₃, 429.2860, observed, 429.2868.

(2S,4R)—N-((3-(4-decylphenyl)-1,2,4-oxadiazol-5-yl)methyl)-4-hydroxypyrrolidine-2-carboxamidehydrochloride 9w

Synthesized according to General Procedure 6. Purified via triturationwith ethyl acetate and diethyl ether. White solid (81%, 79 mg). ¹H NMR(400 MHz, cd₃od) δ 7.93 (d, J=8.3 Hz, 2H), 7.34 (d, J=8.3 Hz, 2H),4.82-4.73 (m, 2H), 4.66-4.54 (m, 2H), 3.43 (dd, J=12.1, 3.5 Hz, 1H),3.36-3.32 (m, 1H), 2.68 (t, J=7.7 Hz, 2H), 2.55 (ddt, J=13.5, 7.6, 1.7Hz, 1H), 2.17 (ddd, J=13.5, 10.4, 4.1 Hz, 1H), 1.65 (p, J=7.5 Hz, 2H),1.43-1.21 (m, 14H), 0.89 (t, J=6.6 Hz, 3H). ¹³C NMR (101 MHz, cd₃od) δ177.73, 170.34, 169.63, 148.22, 130.14, 128.32, 125.14, 71.17, 59.98,55.17, 39.84, 36.84, 36.71, 33.06, 32.43, 30.70, 30.68, 30.55, 30.43,30.29, 23.72, 14.43. HRMS: (ESI) [M+H]+ calc. for C₂₄H₃₇N₄O₃, 429.2860,observed, 429.2862.

(S)—N-((3-(4-decylphenyl)-1,2,4-oxadiazol-5-yl)methyl)pyrrolidine-3-carboxamidehydrochloride (9x)

Synthesized according to General Procedure 6. Purified via triturationwith ethyl acetate and diethyl ether. White solid (78%, 151 mg). ¹H NMR(400 MHz, cd₃od) δ 7.95 (d, J=8.3 Hz, 2H), 7.35 (d, J=8.3 Hz, 2H),4.81-4.67 (m, 2H), 3.60 (dd, J=11.8, 5.4 Hz, 1H), 3.49 (dd, J=11.9, 7.9Hz, 1H), 3.45-3.35 (m, 3H), 2.70 (t, J=7.7 Hz, 2H), 2.49-2.36 (m, 1H),2.33-2.21 (m, 1H), 1.67 (p, J=7.2 Hz, 2H), 1.42-1.24 (m, 14H), 0.92 (t,J=6.7 Hz, 3H). ¹³C NMR (101 MHz, cd₃od) δ 178.13, 174.74, 169.59,148.13, 130.11, 128.31, 125.22, 48.67, 46.56, 43.62, 36.83, 36.64,33.05, 32.42, 30.68, 30.67, 30.54, 30.42, 30.29, 30.21, 23.71, 14.43.HRMS: (ESI) [M+H]+ calc. for C₂₄H₃₇N₄O₂, 413.2911, observed, 413.2903.

(R)-4-amino-N-((3-(4-decylphenyl)-1,2,4-oxadiazol-5-yl)methyl)-3-hydroxybutanamidehydrochloride (9y)

Synthesized according to General Procedure 6. Purified via triturationwith ethyl acetate and diethyl ether. White solid (70%, 90 mg). ¹H NMR(400 MHz, cd₃od) δ 7.93 (d, J=8.3 Hz, 2H), 7.32 (d, J=8.2 Hz, 2H),4.78-4.62 (m, 2H), 4.30-4.19 (m, 1H), 3.16 (dd, J=12.8, 3.2 Hz, 1H),2.94 (dd, J=12.8, 9.2 Hz, 1H), 2.67 (t, J=7.7 Hz, 2H), 2.60-2.57 (m,2H), 1.65 (p, J=7.5 Hz, 2H), 1.38-1.23 (m, 14H), 0.90 (t, J=7.0 Hz, 3H).¹³C NMR (101 MHz, cd₃od) δ 178.22, 173.00, 169.55, 148.09, 130.10,128.32, 125.21, 65.99, 45.46, 41.98, 36.84, 36.49, 33.05, 32.42, 30.69,30.68, 30.55, 30.43, 30.30, 23.72, 14.43. HRMS: (ESI) [M+H]+ calc. forC₂₃H₃₇N₄O₃, 417.2860, observed, 417.2866.

(S)—N-((3-(4-decylphenyl)-1,2,4-oxadiazol-5-yl)methyl)azetidine-2-carboxamide2,2,2-trifluoroacetate (9z)

Synthesized according to General Procedure 5. Purification viatrituration with diethyl ether. White solid (69%, 66 mg). ¹H NMR (400MHz, CDCl₃) δ 8.48-7.80 (m, 3H), 7.27 (d, J=8.1 Hz, 2H), 4.89-4.68 (m,3H), 3.95 (q, J=8.3 Hz, 1H), 3.89-3.79 (m, 1H), 2.65 (t, J=7.7 Hz, 2H),2.56-2.43 (m, 2H), 1.63 (q, J=7.5 Hz, 2H), 1.48 (s, 9H), 1.36-1.22 (m,14H), 0.88 (t, J=6.8 Hz, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 175.65, 172.12,168.53, 157.57, 146.76, 128.97, 127.52, 123.87, 81.35, 62.30, 47.41,36.06, 35.71, 31.99, 31.32, 29.70, 29.67, 29.57, 29.42, 29.37, 28.39,22.78, 19.64, 14.23. HRMS: (ESI) [M+H]+ calc. for C₂₈H₄₃N₄O₄, 499.3279,observed, 499.3277.

methyl(S)-5-amino-6-(((3-(4-decylphenyl)-1,2,4-oxadiazol-5-yl)methyl)amino)-6-oxohexanoatehydrochloride (9aa)

Synthesized according to General Procedure 6. Purification viatrituration with diethyl ether. White solid (58%, 32 mg). ¹H NMR (400MHz, cd₃od) δ 7.95 (d, J=8.3 Hz, 2H), 7.35 (d, J=8.1 Hz, 2H), 4.92-4.68(m, 2H), 4.04 (t, J=6.3 Hz, 1H), 3.67 (s, 3H), 2.70 (t, J=7.7 Hz, 2H),2.47 (t, J=7.1 Hz, 2H), 2.08-1.92 (m, 2H), 1.92-1.77 (m, 2H), 1.67 (p,J=7.2 Hz, 2H), 1.43-1.30 (m, 14H), 0.91 (t, J=6.8 Hz, 3H). ¹³C NMR (101MHz, cd₃od) δ 177.79, 174.91, 170.56, 169.60, 148.14, 130.11, 128.33,125.18, 54.20, 52.16, 36.83, 36.51, 34.00, 33.05, 32.42, 31.90, 30.68,30.67, 30.55, 30.43, 30.29, 23.72, 21.01, 14.44. HRMS: (ESI) [M+H]+calc. for C₂₆H₄₁N₄O₄, 473.3122, observed, 473.3104.

N-((3-(4-decylphenyl)-1,2,4-oxadiazol-5-yl)methyl)-2-(dimethylamino)acetamidehydrochloride (9ab)

Synthesized according to General Procedure 6. Purified via triturationwith ethyl acetate and diethyl ether. White solid (98%, 82 mg). ¹H NMR(400 MHz, cd₃od) δ 7.92 (d, J=8.3 Hz, 2H), 7.32 (d, J=8.3 Hz, 2H), 4.85(s, 2H), 4.13 (s, 2H), 2.99 (s, 6H), 2.67 (t, J=7.7 Hz, 2H), 1.64 (p,J=7.1 Hz, 2H), 1.39-1.21 (m, 14H), 0.89 (t, J=6.7 Hz, 3H). ¹³C NMR (101MHz, cd₃od) δ 177.65, 169.59, 166.39, 148.13, 130.10, 128.30, 125.12,59.14, 44.50, 36.83, 36.48, 33.04, 32.40, 30.69, 30.68, 30.54, 30.42,30.29, 23.71, 14.44. HRMS: (ESI) [M+H]+ calc. for C₂₃H₃₇N₄O₂, 401.2911,observed, 401.2911.

(S)-2-amino-N-((3-(4-decylphenyl)-1,2,4-oxadiazol-5-yl)methyl)-3-phenylpropanamidehydrochloride (9ac)

Synthesized according to General Procedure 6. Purified via triturationwith diethyl ether. White solid (46%, 64 mg). ¹H NMR (400 MHz, cd₃od) δ7.94 (d, J=8.3 Hz, 2H), 7.39-7.21 (m, 8H), 4.82-4.62 (m, 3H), 4.21 (dd,J=7.6, 6.7 Hz, 1H), 3.29 (dd, J=14.1, 6.7 Hz, 1H), 3.14 (dd, J=14.0, 7.6Hz, 1H), 2.68 (t, J=7.4 Hz, 2H), 1.65 (p, J=7.6 Hz, 3H), 1.39-1.22 (m,18H), 0.88 (t, J=7.0 Hz, 2H). ¹³C NMR (101 MHz, cd₃od) δ 177.51, 170.11,169.62, 148.17, 135.33, 130.56, 130.11, 130.08, 128.86, 128.34, 125.18,55.74, 38.51, 36.82, 36.31, 33.02, 32.37, 30.66, 30.66, 30.52, 30.40,30.27, 23.69, 14.41. HRMS: (ESI) [M+H]+ calc. for C₂₈H₃₉N₄O₂, 463.3068,observed, 463.3069.

(S)-2-amino-N-((3-(4-decylphenyl)-1,2,4-oxadiazol-5-yl)methyl)-4-methylpentanamidehydrochloride (9ad)

Synthesized according to General Procedure 6. Purified via triturationwith diethyl ether. White solid (78%, 101 mg). ¹H NMR (400 MHz, cd₃od) δ7.93 (d, J=8.2 Hz, 2H), 7.31 (d, J=8.1 Hz, 2H), 4.84-4.67 (m, 2H), 4.02(dd, J=8.0, 6.0 Hz, 1H), 2.66 (t, J=7.7 Hz, 2H), 1.91-1.71 (m, 3H), 1.64(p, J=7.2 Hz, 2H), 1.39-1.22 (m, 14H), 1.05 (dd, J=8.6, 5.9 Hz, 6H),0.88 (t, J=6.7 Hz, 3H). ¹³C NMR (101 MHz, cd₃od) δ 177.74, 171.27,169.56, 148.10, 130.07, 128.29, 125.16, 52.99, 41.69, 36.83, 36.54,33.04, 32.40, 30.68, 30.67, 30.54, 30.42, 30.29, 25.37, 23.71, 23.00,22.36, 14.45. HRMS: (ESI) [M+H]+ calc. for C₂₅H₄₁N₄O₂, 429.3224,observed, 429.3224.

(2S,4R)—N-((3-(4-decylphenyl)-1,2,4-oxadiazol-5-yl)methyl)-4-fluoropyrrolidine-2-carboxamidehydrochloride (9ae)

Synthesized according to General Procedure 6. Purified via triturationwith ethyl acetate and diethyl ether. White solid (72%, 90 mg). ¹H NMR(400 MHz, cd₃od) δ 7.94 (d, J=8.3 Hz, 2H), 7.34 (d, J=8.1 Hz, 2H), 5.53(dt, J=51.6, 3.5 Hz, 1H), 4.84-4.74 (m, 2H), 4.63 (dd, J=10.5, 7.6 Hz,1H), 3.76-3.56 (m, 2H), 2.94-2.79 (m, 1H), 2.68 (t, J=7.7 Hz, 2H), 2.35(dddd, J=39.0, 14.6, 10.6, 3.8 Hz, 1H), 1.65 (p, J=7.4 Hz, 2H),1.40-1.23 (m, 14H), 0.89 (t, J=6.7 Hz, 3H). ¹³C NMR (101 MHz, cd₃od) δ177.67, 169.58 (d, J=11.8 Hz), 148.23, 130.14, 128.32, 125.12, 93.81 (d,J=177.3 Hz), 59.85, 53.39 (d, J=23.6 Hz), 37.90 (d, J=22.1 Hz), 36.84,36.73, 33.06, 32.43, 30.70, 30.69, 30.55, 30.43, 30.29, 23.72, 14.43.HRMS: (ESI) [M+H]+ calc. for C₂₄H₃₆FN₄O₂, 431.2817, observed, 431.2831.

1-amino-N-((3-(4-decylphenyl)-1,2,4-oxadiazol-5-yl)methyl)cyclopropane-1-carboxamidehydrochloride (9af)

Synthesized according to General Procedure 8 with the followingadaptation. The Boc protected product was immediately deprotectedaccording to General Procedure 6 and purified by silica chromatography(10% methanol in dichloromethane). White solid (50%, 94 mg). ¹H NMR (400MHz, Methanol-d₄) δ 7.92 (d, J=8.2 Hz, 2H), 7.31 (d, J=8.1 Hz, 2H), 4.70(s, 2H), 2.66 (t, J=7.7 Hz, 2H), 1.69-1.59 (m, 4H), 1.55-1.48 (m, 2H),1.36-1.24 (m, 14H), 0.88 (t, J=6.8 Hz, 3H). ¹³C NMR (101 MHz,Methanol-d₄) δ 177.97, 171.56, 169.52, 148.03, 130.05, 128.29, 125.17,36.82, 36.76, 36.52, 33.03, 32.39, 30.68, 30.67, 30.54, 30.42, 30.30,23.71, 14.46, 13.50. HRMS: (ESI) [M+H]+ calc. for C₂₃H₃₅N₄O₂, 399.2755,observed, 399.2742.

(R)—N-((3-(4-decylphenyl)-1,2,4-oxadiazol-5-yl)methyl)piperidine-3-carboxamidehydrochloride (9ag)

Synthesized according to General Procedure 8 with the followingadaptation. The Boc protected product was immediately deprotectedaccording to General Procedure 6 and purified by silica chromatography(10% methanol in dichloromethane). White solid (65%, 91 mg). ¹H NMR (400MHz, Methanol-d₄) δ 7.95 (d, J=8.0 Hz, 2H), 7.34 (d, J=8.0 Hz, 2H), 4.73(q, J=17.0 Hz, 2H), 3.39-3.21 (m, 3H), 3.19-3.08 (m, 1H), 3.00-2.90 (m,1H), 2.69 (t, J=7.7 Hz, 2H), 2.18-2.09 (m, 1H), 2.04-1.81 (m, 3H), 1.67(p, J=7.1 Hz, 2H), 1.38-1.22 (m, 14H), 0.91 (t, J=6.7 Hz, 3H). ¹³C NMR(101 MHz, Methanol-d₄) δ 176.75, 173.78, 168.16, 146.71, 128.69, 126.88,123.81, 44.65, 43.67, 38.02, 35.42, 35.04, 31.64, 31.01, 29.27, 29.26,29.13, 29.01, 28.88, 25.58, 22.30, 20.38, 13.02. HRMS: (ESI) [M+H]+calc. for C₂₅H₃₉N₄O₂, 427.3068, observed, 427.3056.

(1R,3R)-3-amino-N-((3-(4-decylphenyl)-1,2,4-oxadiazol-5-yl)methyl)cyclopentane-1-carboxamidehydrochloride (9ah)

Synthesized according to General Procedure 8 with the followingadaptation. The Boc protected product was immediately deprotectedaccording to General Procedure 6 and purified by silica chromatography(10% methanol in dichloromethane). White solid (73%, 96 mg). ¹H NMR (400MHz, Methanol-d₄) δ 7.95 (d, J=8.2 Hz, 2H), 7.34 (d, J=8.2 Hz, 2H), 4.71(d, J=1.2 Hz, 2H), 3.79-3.71 (m, 1H), 3.14-3.06 (m, 1H), 2.69 (t, J=7.7Hz, 2H), 2.33-2.25 (m, 1H), 2.21-1.93 (m, 2H), 2.09-1.94 (m, 2H),1.90-1.81 (m, 1H), 1.66 (p, J=7.5 Hz, 2H), 1.38-1.23 (m, 14H), 0.90 (t,J=6.8 Hz, 3H). ¹³C NMR (101 MHz, Methanol-d₄) δ 177.95, 176.72, 168.17,146.70, 128.69, 126.88, 123.82, 51.96, 43.16, 35.41, 35.29, 34.25,31.63, 31.01, 30.39, 29.27, 29.26, 29.13, 29.01, 28.87, 28.69, 22.30,13.01. HRMS: (ESI) [M+H]+ calc. for C₂₅H₃₉N₄O₂, 427.3068, observed,427.3065.

(S)-2-amino-1-((R)-3-(3-(4-decylphenyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)-3-methylbutan-1-one2,2,2-trifluoroacetate (9ai)

Synthesized according to General Procedure 8 with the followingadaptation. The Boc protected product was immediately deprotectedaccording to General Procedure 5 and purified by silica chromatography(10% methanol in dichloromethane). Colorless semisolid (89%, 59 mg). ¹HNMR (400 MHz, CD₃OD) δ 8.00-7.86 (m, 2H), 7.37-7.23 (m, 2H), 4.13-3.55(m, 6H), 2.66 (t, J=7.7 Hz, 2H), 2.61-2.31 (m, 2H), 2.17-2.01 (m, 1H),1.63 (p, J=6.9 Hz, 2H), 1.40-1.19 (m, 14H), 1.10-0.97 (m, 6H), 0.88 (t,J=6.7 Hz, 3H). ¹³C NMR (101 MHz, CD₃OD) δ 181.3, 180.8, 169.5, 148.0,130.1, 128.3, 125.3, 58.6, 50.9, 50.6*, 46.7, 46.6*, 38.0, 36.8, 36.0,33.1, 32.4, 31.9*, 31.3, 30.7, 30.6, 30.4, 30.3, 29.3, 23.7. 19.6,19.5*, 17.7, 17.3*, 14.5. HRMS: (ESI) [M+H]+ calc. for C₂₇H₄₃N₄O₂,455.3381, observed, 455.3404.

((S)-2-amino-1-((R)-3-(3-(4-decylphenyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)-3-hydroxypropan-1-one2,2,2-trifluoroacetate (9aj)

Synthesized according to General Procedure 8 with the followingadaptation. The boc protected product was immediately deprotectedaccording to General Procedure 5 and purified by silica chromatography(10% methanol in dichloromethane). White solid (47%, 35 mg). ¹H NMR (400MHz, CD₃OD) δ 7.94 (d, J=7.9 Hz, 2H), 7.31 (d, J=7.9 Hz, 2H), 4.19-3.57(m, 8H), 2.66 (t, J=7.7 Hz, 2H), 2.62-2.30 (m, 2H), 1.63 (p, J=7.1 Hz,2H), 1.40-1.19 (m, 14H), 0.88 (t, J=6.7 Hz, 3H). ¹³C NMR (101 MHz,CD₃OD) δ 181.1, 180.8, 169.5, 148.1, 130.1, 128.3, 125.3, 125.3*, 63.8,63.7*, 55.4, 50.7, 50.6*, 46.7, 46.7*, 37.9, 36.8, 36.0, 33.1, 32.4,31.3, 30.7, 30.6, 30.4, 30.3, 29.4, 23.7, 14.5. HRMS: (ESI) [M+H]+ calc.for C₂₅H₃₉N₄O₃, 443.3017, observed, 443.3026.

(S)-2-amino-1-((R)-3-(3-(4-decylphenyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)propan-1-one2,2,2-trifluoroacetate (9ak)

Synthesized according to General Procedure 8 with the followingadaptation. The boc protected product was immediately deprotectedaccording to General Procedure 5 and purified by silica chromatography(10% methanol in dichloromethane). White solid (41%, 30 mg). ¹H NMR (400MHz, CD₃OD) δ 7.97-7.89 (m, 2H), 7.34-7.27 (m, 2H), 4.07-3.51 (m, 6H),2.66 (t, J=7.5 Hz, 2H), 2.61-2.28 (m, 2H), 1.63 (p, J=6.8 Hz, 2H),1.41-1.19 (m, 14H), 0.88 (t, J=6.8 Hz, 3H). ¹³C NMR (101 MHz, CD₃OD) δ181.2, 180.9*, 175.5, 175.3*, 148.0, 148.0*, 130.1, 128.3, 128.3*,125.3, 125.3*, 50.5, 50.4*, 49.1, 46.5, 46.4*, 38.0, 36.9, 36.0, 33.1,32.4, 31.4, 30.7, 30.6, 30.5, 30.3, 29.5, 23.7, 20.0, 19.9*, 14.5. HRMS:(ESI) [M+H]+ calc. for C₂₅H₃₉N₄O₂, 427.3068, observed, 427.3069.

(R)-2-amino-1-(3-(3-(4-decylphenyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)ethan-1-one2,2,2-trifluoroacetate (9al)

Synthesized according to General Procedure 8 with the followingadaptation. The boc protected product was immediately deprotectedaccording to General Procedure 5 and purified by silica chromatography(10% methanol in dichloromethane). Yellow solid (82%, 141 mg). ¹H NMR(400 MHz, CD₃OD) δ 7.98-7.84 (m, 2H), 7.31-7.20 (m, 2H), 4.06-3.80 (m,5H), 3.78-3.58 (m, 2H), 2.62 (t, J=7.5 Hz, 2H), 2.58-2.25 (m, 2H), 1.60(p, J=6.9 Hz, 2H), 1.36-1.18 (m, 14H), 0.87 (t, J=6.7 Hz, 3H). ¹³C NMR(101 MHz, CD₃OD) δ 180.9, 180.6*, 169.4, 163.2, 162.8*, 147.9, 130.0,128.3, 125.2, 50.4, 49.6, 46.5, 45.9, 41.7, 41.7*, 37.8, 36.8, 36.1*,33.0, 32.4*, 31.2, 30.7, 30.6, 30.4, 30.3, 23.7, 14.5. HRMS: (ESI)[M+H]+ calc. for C₂₄H₃₇N₄O₂, 413.2911, observed, 413.2889.

N-butyl-4-cyanobenzamide (10a)

Synthesized according to General Procedure 8 using 4-cyanobenzonitrile.Purified by silica chromatography (50% ethyl acetate in hexanes). Clearoil (97%, 799 mg). ¹H NMR (400 MHz, Chloroform-d) δ 7.92 (d, J=8.4 Hz,2H), 7.70 (d, J=8.4 Hz, 2H), 7.17 (t, J=5.7 Hz, 1H), 3.43 (q, J=6.9,2H), 1.59 (q, J=7.9 Hz, 2H), 1.38 (h, J=7.3 Hz, 2H), 0.93 (t, J=7.4 Hz,3H). ¹³C NMR (101 MHz, Chloroform-d) δ 165.96, 138.75, 132.22, 127.77,118.05, 114.58, 40.08, 31.42, 20.09, 13.69.

4-cyano-N-octylbenzamide (10b)

Synthesized according to General Procedure 8 using 4-cyanobenzonitrile.Purified by silica chromatography (50% ethyl acetate in hexanes). Clearoil (94%, 822 mg). ¹H NMR (400 MHz, Chloroform-d) δ 7.85 (d, J=8.3 Hz,2H), 7.72 (d, J=8.3 Hz, 2H), 6.29 (t, J=5.9 Hz, 1H), 3.44 (q, J=7.3 Hz,2H), 1.61 (p, J=7.4 Hz, 2H), 1.40-1.22 (m, 10H), 0.86 (t, J=6.8 Hz, 3H).¹³C NMR (101 MHz, Chloroform-d) δ 165.82, 138.88, 132.53, 127.72,118.17, 115.01, 40.52, 31.89, 29.65, 29.37, 29.31, 27.10, 22.76, 14.22.HRMS: (ESI) [M+H]+ calc. for C₁₆H₂₃N₂O, 259.1805, observed, 259.1804.

N-butyl-4-(N′-hydroxycarbamimidoyl)benzamide (11a)

Synthesized according to General Procedure 3. Purified by silicachromatography (90% ethyl acetate in hexanes). White solid (61%, 554mg). ¹H NMR (400 MHz, Methanol-d₄) δ 7.84 (d, J=8.5 Hz, 2H), 7.74 (d,J=8.5 Hz, 2H), 3.39 (t, J=7.2 Hz, 2H), 1.62 (p, J=7.3 Hz, 2H), 1.43 (h,J=7.3 Hz, 2H), 0.99 (t, J=7.4 Hz, 3H). ¹³C NMR (101 MHz, Methanol-d₄) δ169.50, 154.45, 137.13, 136.79, 128.30, 127.25, 40.79, 32.61, 21.19,14.14.

4-(N′-hydroxycarbamimidoyl)-N-octylbenzamide (11b)

Synthesized according to General Procedure. Purified by silicachromatography (90% ethyl acetate in hexanes). White solid (52%, 555mg). ¹H NMR (400 MHz, Methanol-d₄) δ 7.87 (d, J=8.3 Hz, 2H), 7.77 (d,J=8.5 Hz, 2H), 3.41 (t, J=7.2 Hz, 2H), 1.66 (p, J=7.1 Hz, 2H), 1.47-1.30(m, 10H), 0.93 (t, J=6.8 Hz, 3H). ¹³C NMR (101 MHz, Methanol-d₄) δ169.52, 162.59, 137.16, 136.83, 128.30, 127.26, 41.09, 32.99, 30.48,30.43, 30.37, 28.11, 23.70, 14.41.

tert-butyl(R)-3-(3-(4-(butylcarbamoyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboxylate(12a)

Synthesized according to General Procedure 4. Purified by silicachromatography (60% ethyl acetate in hexanes). Yellow solid (67%, 329mg). ¹H NMR (400 MHz, Chloroform-d) δ 8.08 (d, J=8.1 Hz, 2H), 7.85 (d,J=8.2 Hz, 2H), 6.54 (t, J=5.7 Hz, 1H), 3.88-3.54 (m, 4H), 3.52-3.40 (m,3H), 2.43-4.28 (m, 2H), 1.59 (p, J=8.0, 2H), 1.45 (s, 9H), 1.38 (h,J=7.4 Hz, 2H), 0.93 (t, J=7.3 Hz, 3H). ¹³C NMR (101 MHz, Chloroform-d) δ179.87, 167.78, 166.82, 154.27, 137.37, 129.25, 127.63, 127.55, 79.90,49.44, 49.23, 45.34, 45.11, 40.04, 36.65, 35.86, 31.76, 30.44, 29.67,28.55, 20.25, 13.87.

tert-butyl(3-(3-(4-(butylcarbamoyl)phenyl)-1,2,4-oxadiazol-5-yl)propyl)carbamate(12b)

Synthesized according to General Procedure 4. Purified by silicachromatography (55% ethyl acetate in hexanes). White solid (52%, 251mg). ¹H NMR (400 MHz, Chloroform-d) δ 8.10 (d, J=8.4 Hz, 2H), 7.85 (d,J=8.4 Hz, 2H), 6.32 (t, J=5.8 Hz, 1H), 4.82 (s, 1H), 3.46 (td, J=7.2,5.7 Hz, 2H), 3.28 (q, J=6.5 Hz, 2H), 2.99 (t, J=7.5 Hz, 2H), 2.08 (p,J=7.1 Hz, 2H), 1.67-1.54 (m, 2H), 1.46-1.36 (m, 11H), 0.95 (t, J=7.3 Hz,3H). ¹³C NMR (101 MHz, Chloroform-d) δ 179.78, 167.71, 166.84, 156.09,137.27, 129.56, 127.67, 127.52, 79.56, 40.07, 39.85, 31.82, 28.50,27.05, 24.17, 20.30, 13.91.

tert-butyl(R)-3-(3-(4-(octylcarbamoyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboxylate(12c)

Synthesized according to General Procedure 4. Purified by silicachromatography (60% ethyl acetate in hexanes). White solid (69%, 329mg). ¹H NMR (400 MHz, Chloroform-d) δ 8.00 (d, J=8.0 Hz, 2H), 7.83 (d,J=8.0 Hz, 2H), 7.03 (t, J=5.7 Hz, 1H), 3.85-3.75 (m, 1H), 3.71-3.50 (m,3H), 3.47-3.31 (m, 3H), 2.38-2.22 (m, 2H), 1.54 (p, J=7.4 Hz, 2H), 1.40(s, 9H), 1.33-1.08 (m, 10H), 0.79 (t, J=6.7 Hz, 3H). ¹³C NMR (101 MHz,Chloroform-d) δ 179.72, 167.64, 166.79, 154.16, 137.30, 129.02, 127.55,127.39, 79.76, 49.03, 45.03, 40.27, 36.05, 31.74, 30.27, 29.56, 29.26,29.16, 28.42, 27.01, 22.57, 14.04.

tert-butyl(3-(3-(4-(octylcarbamoyl)phenyl)-1,2,4-oxadiazol-5-yl)propyl)carbamate(12d)

Synthesized according to General Procedure 4. Purified by silicachromatography (60% ethyl acetate in hexanes). White solid (48%, 188mg). ¹H NMR (400 MHz, Chloroform-d) δ 8.04 (d, J=8.0 Hz, 2H), 7.83 (d,J=8.0 Hz, 2H), 6.68 (t, J=5.6 Hz, 1H), 4.97 (s, 1H), 3.40 (q, J=6.8 Hz,2H), 3.24 (q, J=6.5 Hz, 2H), 2.95 (t, J=7.4 Hz, 2H), 2.03 (p, J=7.0 Hz,2H), 1.57 (p, J=7.3 Hz, 2H), 1.39 (s, 9H), 1.36-1.17 (m, 10H), 0.83 (t,J=6.5 Hz, 3H). ¹³C NMR (101 MHz, Chloroform-d) δ 179.68, 167.61, 166.85,156.08, 137.23, 129.40, 127.52, 127.50, 79.41, 40.34, 39.77, 31.83,29.66, 29.34, 29.25, 28.43, 27.09, 26.94, 24.08, 22.67, 14.12.

(R)—N-butyl-4-(5-(pyrrolidin-3-yl)-1,2,4-oxadiazol-3-yl)benzamidehydrochloride (13a)

Synthesized according to General Procedure 6. Purified via triturationwith diethyl ether. White solid (36%, 102 mg). ¹H NMR (400 MHz,Methanol-d₄) δ 8.11 (d, J=8.4 Hz, 2H), 7.93 (d, J=8.4 Hz, 2H), 3.91 (p,J=8.2, 1H), 3.65-3.58 (m, 1H), 3.53-3.47 (m, 1H), 3.39 (t, J=7.2 Hz,2H), 3.36-3.26 (m, 2H) 2.49 (h, J=7.9 Hz, 1H), 2.34 (h, J=7.8 Hz, 1H),1.60 (q, J=7.9 Hz, 2H), 1.41 (h, J=7.3 Hz, 2H), 0.96 (t, J=7.3 Hz, 3H).¹³C NMR (101 MHz, Methanol-d₄) δ 182.13, 169.06, 168.85, 138.45, 130.56,128.90, 128.40, 50.86, 47.13, 40.83, 37.41, 32.57, 31.43, 21.19, 14.15.HRMS: (ESI) [M+H]+ calc. for C₁₇H₂₃N₄O₂, 315.1816, observed, 315.18225.

4-(5-(3-aminopropyl)-1,2,4-oxadiazol-3-yl)-N-butylbenzamidehydrochloride (13b)

Synthesized according to General Procedure 6. Purified via triturationwith diethyl ether. White solid (38%, 80 mg). ¹H NMR (400 MHz,Methanol-d₄) δ 8.16 (d, J=8.4 Hz, 2H), 7.99 (d, J=8.5 Hz, 2H), 3.43 (t,J=7.2 Hz, 2H), 3.20 (t, J=7.5 Hz, 4H), 2.31 (p, J=7.5 Hz, 2H), 1.66 (p,J=7.3 Hz, 2H), 1.46 (h, J=7.3 Hz, 2H), 1.01 (t, J=7.4 Hz, 3H). ¹³C NMR(101 MHz, Methanol-d₄) δ 180.69, 169.12, 168.84, 138.42, 130.69, 128.93,128.37, 40.83, 39.85, 32.58, 25.11, 24.33, 21.20, 14.15.

(R)—N-octyl-4-(5-(pyrrolidin-3-yl)-1,2,4-oxadiazol-3-yl)benzamidehydrochloride (13c)

Synthesized according to General Procedure 6. Purified via triturationwith diethyl ether. White solid. ¹H NMR (400 MHz, cd₃od) δ 8.61 (t,J=5.7 Hz, 1H), 8.16 (d, J=8.5 Hz, 2H), 7.95 (d, J=8.5 Hz, 2H), 4.19-4.07(m, 1H), 3.90-3.75 (m, 2H), 3.62-3.46 (m, 2H), 3.44-3.33 (m, 2H),2.72-2.58 (m, 1H), 2.54-2.41 (m, 1H), 1.64 (p, J=7.7 Hz, 2H), 1.46-1.27(m, 10H), 0.90 (t, J=7.1 Hz, 3H). ¹³C NMR (101 MHz, cd₃od) δ 180.55,169.18*, 169.11, 169.02, 138.70*, 138.66, 130.41, 128.96, 128.48, 49.47,46.62, 41.28, 41.26*, 41.16, 36.68, 32.99, 30.45, 30.43, 30.38, 28.11,23.71, 14.43.

4-(5-(3-aminopropyl)-1,2,4-oxadiazol-3-yl)-N-octylbenzamidehydrochloride (13d)

Synthesized according to General Procedure 6. Purified via triturationwith diethyl ether. White solid (96%, 155 mg). ¹H NMR (400 MHz,Methanol-d₄) δ 8.15 (d, J=8.4 Hz, 2H), 7.95 (d, J=8.4 Hz, 2H), 3.40 (t,J=7.2 Hz, 2H), 3.19-3.13 (m, 4H), 2.26 (p, J=7.5 Hz, 2H), 1.64 (p, J=7.2Hz, 2H), 1.44-1.28 (m, 10H), 0.89 (t, J=6.8 Hz, 3H). ¹³C NMR (101 MHz,Methanol-d₄) δ 179.22, 167.71, 167.46, 137.10, 129.25, 127.49, 126.94,39.71, 38.40, 31.55, 29.01, 28.98, 28.93, 26.67, 23.75, 22.83, 22.26,12.98. HRMS: (ESI) [M+H]+ calc. for C₂₀H₃₁N₄O₂, 359.2442, observed,359.2432.

methyl 3-(4-decylphenyl)-1,2,4-oxadiazole-5-carboxylate (14)

Synthesized according to General Procedure 9 from 3a. Purified on silicagel (10% ethyl acetate/hexanes). White solid (0.79 g, 64%). ¹H NMR (400MHz, Chloroform-d) δ 8.05 (d, J=8.1 Hz, 2H), 7.31 (d, J=8.1 Hz, 2H),4.11 (s, 3H), 2.67 (t, J=7.8 Hz, 2H), 1.64 (p, J=7.4 Hz, 2H), 1.38-1.18(m, 14H), 0.87 (t, J=6.8 Hz, 3H); ¹³C NMR (101 MHz, Chloroform-d) δ169.68, 166.30, 154.81, 147.58, 129.23, 127.77, 123.04, 54.27, 36.15,32.04, 31.32, 29.75, 29.71, 29.61, 29.47, 29.42, 22.83, 14.26; HRMS(ESI+): Calcd for C₂₀H₂₉N₂O₃ [M+H]⁺: 345.2173, Found: 345.2170.

tert-butyl(2-(3-(4-decylphenyl)-1,2,4-oxadiazole-5-carboxamido)ethyl)carbamate(15a)

Synthesized according to General Procedure 10 from 14. Purified onsilica gel (30% ethyl acetate/hexanes). White solid (0.23 g, 85%). ¹HNMR (400 MHz, Chloroform-d) δ 8.06 (t, J=5.8 Hz, 1H), 7.97 (d, J=8.0 Hz,2H), 7.27 (d, J=8.2 Hz, 2H), 5.11 (t, J=6.1 Hz, 1H), 3.62 (q, J=5.5 Hz,2H), 3.43 (q, J=5.9 Hz, 2H), 2.64 (t, J=7.8 Hz, 2H), 1.62 (p, J=7.4 Hz,2H), 1.42 (s, 9H), 1.37-1.13 (m, 14H), 0.86 (t, J=6.8 Hz, 3H); ¹³C NMR(101 MHz, Chloroform-d) δ 168.89, 168.52, 157.14, 153.89, 147.31,129.10, 127.60, 123.20, 80.19, 41.50, 39.75, 36.09, 32.00, 31.29, 29.71,29.68, 29.57, 29.43, 29.39, 28.40, 22.79, 14.23; HRMS (ESI+): Calcd forC₂₁H₃₃N₄O₂ [M+H-Boc]*: 373.2598, Found: 373.2611.

tert-butyl(3-(3-(4-decylphenyl)-1,2,4-oxadiazole-5-carboxamido)propyl)carbamate(15b)

Synthesized according to General Procedure 10 from 14. Purified onsilica gel (30% ethyl acetate/hexanes). White solid (0.20 g, 95%). ¹HNMR (400 MHz, Chloroform-d) δ 8.00 (d, J=7.9 Hz, 2H), 7.98-7.93 (m, 1H),7.29 (d, J=8.1 Hz, 2H), 4.95 (t, J=6.9 Hz, 1H), 3.56 (q, J=6.4 Hz, 2H),3.25 (q, J=6.3 Hz, 2H), 2.65 (t, J=7.7 Hz, 2H), 1.79 (p, J=6.2 Hz, 2H),1.63 (p, J=7.0 Hz, 2H), 1.45 (s, 9H), 1.34-1.20 (m, 14H), 0.87 (t, J=6.7Hz, 3H); ¹³C NMR (101 MHz, Chloroform-d) δ 168.93, 168.69, 156.88,153.67, 147.31, 129.14, 127.66, 123.28, 79.73, 37.32, 36.85, 36.11,32.01, 31.32, 30.11, 29.72, 29.69, 29.59, 29.44, 29.39, 28.50, 22.80,14.24.

N-(2-aminoethyl)-3-(4-decylphenyl)-1,2,4-oxadiazole-5-carboxamidehydrochloride (16a)

Synthesized according to General Procedure 6. Purified on silica gel(10% methanol/dichloromethane). White solid (0.17 g, 96%). ¹H NMR (400MHz, Methylene Chloride-d₂) δ 8.00 (d, J=8.0 Hz, 2H), 7.33 (d, J=8.0 Hz,2H), 3.75 (t, J=5.9 Hz, 2H), 3.21 (t, J=5.9 Hz, 2H), 2.67 (t, J=7.7 Hz,2H), 1.63 (p, J=7.3 Hz, 2H), 1.45-1.14 (m, 14H), 0.86 (t, J=6.8 Hz, 3H);¹³C NMR (101 MHz, Methylene Chloride-d₂) δ 169.56, 168.96, 155.43,148.11, 129.65, 127.86, 123.64, 39.61, 37.80, 36.38, 32.40, 31.74,30.09, 30.07, 29.95, 29.82, 29.74, 23.16, 14.22; HRMS (ESI+): Calcd forC₂₁H₃₃N₄O₂ [M+H]⁺: 373.2598, Found: 373.2602.

N-(3-aminopropyl)-3-(4-decylphenyl)-1,2,4-oxadiazole-5-carboxamidehydrochloride (16b)

Synthesized according to General Procedure 6. Purified on silica gel(10% methanol/dichloromethane). White solid (0.14 g, 90%). ¹H NMR (400MHz, Methanol-d₄) δ 8.00 (d, J=7.8 Hz, 2H), 7.34 (d, J=7.9 Hz, 2H), 3.55(t, J=6.6 Hz, 2H), 3.06 (t, J=7.6 Hz, 2H), 2.67 (t, J=7.7 Hz, 2H), 2.03(p, J=7.0 Hz, 2H), 1.64 (p, J=7.1 Hz, 2H), 1.42-1.16 (m, 14H), 0.88 (t,J=6.5 Hz, 3H); ¹³C NMR (101 MHz, Methanol-d₄) δ 170.15, 155.86, 148.56,130.21, 128.47, 124.65, 38.45, 37.71, 36.86, 33.06, 32.41, 30.70, 30.56,30.45, 30.31, 28.44, 23.73, 14.46; HRMS (ESI+): Calcd for C₂₂H₃₅N₄O₂[M+H]⁺: 387.2755, Found: 387.2737.

(9H-fluoren-9-yl)methyl tert-butyl(1-(3-(4-decylphenyl)-1,2,4-oxadiazol-5-yl)pentane-1,5-diyl)(S)-dicarbamate(17a)

Synthesized according to General Procedure 4. Purified by silica gel(30% ethyl acetate/hexane). White Solid (0.36 g, 73%). ¹H NMR (400 MHz,Chloroform-d) δ 7.97 (d, J=7.9 Hz, 2H), 7.76 (d, J=7.6 Hz, 2H), 7.62 (t,J=7.0 Hz, 2H), 7.40 (t, J=7.5 Hz, 2H), 7.32 (dd, J=7.2, 2.7 Hz, 2H),7.28 (d, J=8.2 Hz, 2H), 5.71 (d, J=8.6 Hz, 1H), 5.15 (q, J=7.7 Hz, 1H),4.62 (t, J=6.8 Hz, 1H), 4.49 (dd, J=10.6, 6.9 Hz, 1H), 4.46-4.37 (m,1H), 4.24 (t, J=7.0 Hz, 1H), 3.13 (q, J=7.2 Hz, 2H), 2.66 (t, J=7.7 Hz,2H), 2.13-1.89 (m, 2H), 1.65 (p, J=14.8, 7.4 Hz, 2H), 1.58-1.48 (m, 2H),1.43 (s, 11H), 1.36-1.18 (m, 14H), 0.88 (t, J=6.8 Hz, 3H); ¹³C NMR (101MHz, Chloroform-d) δ 178.99, 168.41, 156.26, 155.97, 146.82, 143.88,143.73, 141.41, 129.03, 127.84, 127.58, 127.20, 125.20, 125.16, 123.89,120.10, 79.37, 67.30, 48.87, 47.26, 40.00, 36.08, 33.62, 32.01, 31.34,29.72, 29.70, 29.65, 29.59, 29.44, 29.37, 28.52, 22.80, 22.46, 14.25;HRMS (ESI+): Calcd for C₄₃H₅₇N₄O₅ [M+H]⁺: 709.4323, Found: 709.4322.

(9H-fluoren-9-yl)methyl tert-butyl(1-(3-(4-decylphenyl)-1,2,4-oxadiazol-5-yl)butane-1,4-diyl)(S)-dicarbamate(17b)

Synthesized according to General Procedure 4. Purified by silica gel(30% ethyl acetate/hexanes). Yellow solid (0.20 g, 40%). ¹H NMR (400MHz, Chloroform-d) δ 7.97 (d, J=8.0 Hz, 2H), 7.76 (d, J=7.6 Hz, 2H),7.62 (t, J=7.3 Hz, 2H), 7.40 (t, J=7.5 Hz, 2H), 7.34-7.30 (m, 2H), 7.28(d, J=8.2 Hz, 2H), 5.85-5.70 (m, 1H), 5.27-5.09 (m, 1H), 4.64 (s, 1H),4.51-4.42 (m, 2H), 4.24 (t, J=7.0 Hz, 1H), 3.27-3.13 (m, 2H), 2.66 (t,J=7.7 Hz, 2H), 2.14-2.00 (m, 1H), 1.99-1.87 (m, 1H), 1.70-1.62 (m, 2H),1.61-1.54 (m, 2H), 1.45 (s, 9H), 1.39-1.19 (m, 14H), 0.88 (t, J=6.8 Hz,3H); ¹³C NMR (101 MHz, Chloroform-d) δ 178.82, 168.46, 156.23, 155.94,146.88, 143.91, 143.73, 141.46, 129.06, 127.87, 127.60, 127.22, 125.20,123.87, 120.12, 79.56, 67.27, 48.85, 47.31, 39.91, 36.09, 32.02, 31.33,31.26, 29.73, 29.70, 29.60, 29.45, 29.38, 28.52, 26.34, 22.81, 14.24.

(9H-fluoren-9-yl)methyl tert-butyl(1-(3-(4-decylphenyl)-1,2,4-oxadiazol-5-yl)propane-1,3-diyl)(S)-dicarbamate(17c)

Synthesized according to General procedure 4. Purified by silica gel(25% ethyl acetate/hexanes). White solid (0.36 g, 74%). ¹H NMR (400 MHz,Chloroform-d) δ 7.96 (d, J=7.9 Hz, 2H), 7.77 (d, J=7.6 Hz, 2H),7.69-7.59 (m, 2H), 7.40 (t, J=7.5 Hz, 2H), 7.33 (dd, J=7.1, 2.7 Hz, 2H),7.28 (d, J=8.2 Hz, 2H), 6.00 (d, J=9.0 Hz, 1H), 5.24 (q, J=7.9 Hz, 1H),4.93 (t, J=6.7 Hz, 1H), 4.49 (d, J=7.0 Hz, 2H), 4.26 (t, J=7.0 Hz, 1H),3.59-3.36 (m, 1H), 3.16-2.98 (m, 1H), 2.66 (t, J=7.7 Hz, 2H), 2.32-2.19(m, 1H), 2.19-2.02 (m, 1H), 1.64 (p, J=7.2 Hz, 2H), 1.42 (s, 9H),1.35-1.19 (m, 14H), 0.88 (t, J=6.8 Hz, 3H); ¹³C NMR (101 MHz,Chloroform-d) δ 178.76, 168.47, 156.29, 156.19, 146.88, 143.87, 143.70,141.46, 129.05, 127.89, 127.60, 127.24, 125.23, 123.86, 120.13, 79.84,67.39, 47.32, 46.75, 36.47, 36.10, 34.37, 32.03, 31.34, 29.74, 29.71,29.61, 29.46, 29.38, 28.48, 22.82, 14.25.

(9H-fluoren-9-yl)methyl tert-butyl(1-(3-(4-decylphenyl)-1,2,4-oxadiazol-5-yl)pentane-1,5-diyl)(R)-dicarbamate(18d)

Synthesized according to General Procedure 4. Crude mixture concentratedand carried forward without further purification.

tert-butyl(S)-(5-amino-5-(3-(4-decylphenyl)-1,2,4-oxadiazol-5-yl)pentyl)carbamate(18a)

Synthesized according to General Procedure 11. Purified by silica gel(5% methanol/dichloromethane). Yellow oil (0.06 g, 85%). ¹H NMR (400MHz, Chloroform-d) δ 7.96 (d, J=7.9 Hz, 2H), 7.27 (d, J=8.1 Hz, 2H),4.58 (s, 1H), 4.19 (t, J=6.8 Hz, 1H), 3.12 (q, J=6.5 Hz, 2H), 2.64 (t,J=7.7 Hz, 2H), 2.01-1.92 (m, 2H), 1.91-1.78 (m, 2H), 1.62 (p, J=7.4 Hz,2H), 1.58-1.51 (m, 2H), 1.50-1.44 (m, 2H), 1.41 (s, 9H), 1.34-1.20 (m,14H), 0.86 (t, J=6.7 Hz, 3H); ¹³C NMR (101 MHz, Chloroform-d) δ 182.47,168.31, 156.06, 146.68, 129.03, 127.51, 124.14, 79.22, 49.32, 40.35,36.07, 35.66, 32.01, 31.35, 29.86, 29.72, 29.69, 29.59, 29.44, 29.36,28.51, 22.96, 22.80, 14.24; HRMS (ESI+): Calcd for C₂₈H₄₇N₄O₃ [M+H]⁺:487.3643, Found: 487.3632.

tert-butyl(S)-(4-amino-4-(3-(4-decylphenyl)-1,2,4-oxadiazol-5-yl)butyl)carbamate(18b)

Synthesized according to General Procedure 11. Purified by silica gel(5% methanol/dichloromethane). Yellow oil (0.03 g, 83%). ¹H NMR (400MHz, Chloroform-d) δ 7.97 (d, J=8.1 Hz, 2H), 7.28 (d, J=8.1 Hz, 2H),4.69 (s, 1H), 4.24 (t, J=6.9 Hz, 1H), 3.18 (q, J=6.7 Hz, 2H), 2.65 (t,J=7.7 Hz, 2H), 2.22-2.02 (m, OH), 2.01-1.80 (m, 2H), 1.74-1.63 (m, 2H),1.63-1.57 (m, 2H), 1.43 (s, 9H), 1.36-1.14 (m, 14H), 0.87 (t, J=6.6 Hz,3H); ¹³C NMR (101 MHz, Chloroform-d) δ 182.25, 168.36, 156.11, 146.75,129.05, 127.53, 124.12, 79.38, 49.12, 40.19, 36.09, 33.14, 32.03, 31.35,29.73, 29.71, 29.61, 29.45, 29.39, 28.54, 26.43, 22.81, 14.25; HRMS(ESI+): Calcd for C₂₇H₄₅N₄O₃ [M+H]⁺: 473.3486, Found: 473.3476.

tert-butyl(S)-(3-amino-3-(3-(4-decylphenyl)-1,2,4-oxadiazol-5-yl)propyl)carbamate(18c)

Synthesized according to General Procedure 11. Purified by silica gel(5% methanol/dichloromethane). Yellow oil (0.02 g, 34%). ¹H NMR (400MHz, Chloroform-d) δ 7.96 (d, J=8.0 Hz, 2H), 7.28 (d, J=8.1 Hz, 2H),5.06 (s, 1H), 4.28 (dd, J=8.7, 5.0 Hz, 1H), 3.55-3.39 (m, 1H), 3.38-3.20(m, 1H), 2.65 (t, J=7.7 Hz, 2H), 2.28-2.11 (m, 2H), 2.11-1.90 (m, 2H),1.63 (p, J=7.2 Hz, 2H), 1.42 (s, 9H), 1.34-1.13 (m, 14H), 0.87 (t, J=6.5Hz, 3H); ¹³C NMR (101 MHz, Chloroform-d) δ 182.09, 168.39, 156.18,146.77, 129.06, 127.54, 124.09, 79.55, 47.71, 37.57, 36.10, 35.84,32.03, 31.35, 29.74, 29.71, 29.61, 29.46, 29.39, 28.52, 22.82, 14.25;HRMS (ESI+): Calcd for C₂₆H₄₃N₄O₃ [M+H]⁺: 459.3330, Found: 459.3325.

tert-butyl(R)-(5-amino-5-(3-(4-decylphenyl)-1,2,4-oxadiazol-5-yl)pentyl)carbamate(18d)

Synthesized according to General Procedure 11. Purified by silica gel(50% ethyl acetate/hexanes). Yellow solid (0.12 g, 44%). ¹H NMR (400MHz, Chloroform-d) δ 7.96 (d, J=8.2 Hz, 2H), 7.27 (d, J=8.1 Hz, 2H),4.59 (s, 1H), 4.19 (t, J=6.8 Hz, 1H), 3.11 (q, J=6.4 Hz, 2H), 2.64 (t,J=7.7 Hz, 2H), 2.05-1.85 (m, 2H), 1.83 (s, 2H), 1.62 (p, J=7.4 Hz, 2H),1.58-1.50 (m, 2H), 1.50-1.43 (m, 2H), 1.41 (s, 9H), 1.33-1.16 (m, 14H),0.86 (t, J=6.6 Hz, 3H); ¹³C NMR (101 MHz, Chloroform-d) δ 182.48,168.32, 156.07, 146.68, 129.02, 127.51, 124.16, 79.20, 49.32, 40.35,36.07, 35.67, 32.00, 31.33, 29.87, 29.71, 29.68, 29.58, 29.43, 29.36,28.52, 22.96, 22.79, 14.23; HRMS (ESI+): Calcd for C₂₈H₄₇N₄O₃ [M+H]⁺:487.3643, Found: 487.3634.

(S)-1-(3-(4-decylphenyl)-1,2,4-oxadiazol-5-yl)pentane-1,5-diaminehydrochloride (19a)

Synthesized according to General Procedure 6. Purified by triturationwith diethyl ether. White solid (0.02 g, 37%). ¹H NMR (400 MHz,Methanol-d₄) δ 7.97 (d, J=8.1 Hz, 2H), 7.34 (d, J=8.1 Hz, 2H), 4.29 (t,J=6.8 Hz, 1H), 3.01-2.89 (m, 2H), 2.68 (t, J=7.7 Hz, 2H), 2.09-1.87 (m,2H), 1.78-1.65 (m, 2H), 1.70-1.59 (m, 2H), 1.62-1.41 (m, 2H), 1.39-1.19(m, 14H), 0.89 (t, J=6.8 Hz, 3H); ¹³C NMR (101 MHz, Methanol-d₄) δ183.10, 169.43, 148.11, 130.12, 128.34, 125.35, 49.72, 40.45, 36.84,35.77, 33.07, 32.47, 30.71, 30.57, 30.46, 30.31, 28.22, 23.74, 23.52,14.45; HRMS (ESI+): Calcd for C₂₃H₃₉N₄O [M+H]⁺: 387.3118, Found:387.3124.

(S)-1-(3-(4-decylphenyl)-1,2,4-oxadiazol-5-yl)butane-1,4-diaminedihydrochloride (19b)

Synthesized according to General Procedure 6. Purified by silica gel(0%-20% methanol/dichloromethane). White solid (0.01 g, 57%). ¹H NMR(400 MHz, Methanol-d₄) δ 7.98 (d, J=8.0 Hz, 2H), 7.35 (d, J=8.0 Hz, 2H),4.54 (t, J=6.8 Hz, 1H), 3.02 (t, J=7.4 Hz, 2H), 2.69 (t, J=7.7 Hz, 2H),2.24-1.99 (m, 2H), 1.94-1.75 (m, 2H), 1.65 (p, J=7.3 Hz, 2H), 1.42-1.19(m, 14H), 0.89 (t, J=6.8 Hz, 3H); ¹³C NMR (101 MHz, Methanol-d₄) δ180.76, 169.60, 148.30, 130.16, 128.40, 125.07, 49.26, 40.24, 36.84,33.05, 32.42, 32.28, 30.69, 30.55, 30.43, 30.29, 24.85, 23.72, 14.44;HRMS (ESI+): Calcd for C₂₂H₃₇N₄O [M+H]⁺: 373.2962, Found: 373.2955.

(S)-1-(3-(4-decylphenyl)-1,2,4-oxadiazol-5-yl)propane-1,3-diaminedihydrochloride (19c)

Synthesized according to General Procedure 6. Purified by silica gel(0%-20% methanol/dichloromethane). White solid (0.02 g, 67%). ¹H NMR(400 MHz, Methanol-d₄) δ 7.97 (d, J=8.2 Hz, 2H), 7.34 (d, J=8.1 Hz, 2H),4.39 (dd, J=8.8, 5.1 Hz, 1H), 3.28-3.15 (m, 2H), 2.68 (t, J=7.7 Hz, 2H),2.38-2.26 (m, 1H), 2.22-2.08 (m, 1H), 1.66 (p, J=7.5 Hz, 2H), 1.42-1.19(m, 14H), 0.89 (t, J=6.9 Hz, 3H); ¹³C NMR (101 MHz, Methanol-d₄) δ182.80, 169.50, 148.14, 130.12, 128.35, 125.31, 48.60, 38.62, 36.84,33.29, 33.06, 32.44, 30.69, 30.55, 30.44, 30.30, 23.72, 14.43; HRMS(ESI+): Calcd for C₂₁H₃₅N₄O [M+H]⁺: 359.2805, Found: 359.2798.

(R)-1-(3-(4-decylphenyl)-1,2,4-oxadiazol-5-yl)pentane-1,5-diaminedihydrochloride (19

Synthesized according to General Procedure 6. Purified by triturationwith diethyl ether. White solid (0.09 g, 79%). ¹H NMR (400 MHz,Methanol-d₄) δ 8.01 (d, J=8.0 Hz, 2H), 7.35 (d, J=8.1 Hz, 2H), 4.98 (t,J=6.9 Hz, 1H), 2.99 (t, J=7.6 Hz, 2H), 2.68 (t, J=7.7 Hz, 2H), 2.34-2.14(m, 2H), 1.80 (p, J=7.6 Hz, 2H), 1.72-1.63 (m, 2H), 1.63-1.53 (m, 2H),1.40-1.20 (m, 14H), 0.88 (t, J=6.9 Hz, 3H); ¹³C NMR (101 MHz,Methanol-d₄) δ 176.69, 169.75, 148.48, 130.18, 128.48, 124.60, 48.85,40.21, 36.83, 33.01, 32.36, 30.66, 30.52, 30.40, 30.27, 27.82, 23.69,23.05, 14.46; HRMS (ESI+): Calcd for C₂₃H₃₉N₄O [M+H]⁺: 387.3118, Found:387.3106.

tert-butyl(S)-(5-acetamido-5-(3-(4-decylphenyl)-1,2,4-oxadiazol-5-yl)pentyl)carbamate(20)

18a (1 equiv) and TEA (3 equiv) were added to a round bottom flaskcontaining DCM. Acetyl chloride (1.1 equiv) was added and the reactionmixture was stirred at room temperature for 4 hours. Concentration invacuo afforded the crude product, which was then purified by columnchromatography using the appropriate ethyl acetate and hexanes solventsystem to afford the acetyl protected compound. Purified by silica gel(60% ethyl acetate/hexanes). White solid (0.08 g, 48%). ¹H NMR (400 MHz,Chloroform-d) δ 7.93 (d, J=7.9 Hz, 2H), 7.25 (d, J=8.4 Hz, 2H), 6.71 (d,J=8.1 Hz, 1H), 5.36 (q, J=7.3 Hz, 1H), 4.67 (t, J=6.2 Hz, 1H), 3.09 (q,J=6.5 Hz, 2H), 2.63 (t, J=7.7 Hz, 2H), 2.07 (s, 3H), 2.04-1.84 (m, 2H),1.61 (p, J=7.3 Hz, 2H), 1.54-1.46 (m, 2H), 1.41 (s, 9H), 1.39-1.33 (m,2H), 1.33-1.20 (m, 14H), 0.86 (t, J=6.8 Hz, 3H); ¹³C NMR (101 MHz,Chloroform-d) δ 178.97, 170.16, 168.35, 156.33, 146.75, 128.99, 127.51,123.89, 79.27, 46.83, 39.86, 36.04, 33.28, 31.98, 31.31, 29.69, 29.67,29.56, 29.41, 29.34, 28.49, 23.13, 22.77, 22.40, 14.22.

(S)—N-(5-amino-1-(3-(4-decylphenyl)-1,2,4-oxadiazol-5-yl)pentyl)acetamidehydrochloride (21)

Synthesized according to General Procedure 6. Purified by silica gel(0%-20% methanol/dichloromethane). White solid (0.06 g, 85%). ¹H NMR(400 MHz, Methanol-d₄) δ 7.95 (d, J=8.2 Hz, 2H), 7.33 (d, J=8.1 Hz, 2H),5.28 (dd, J=8.8, 5.9 Hz, 1H), 2.95 (t, J=7.6 Hz, 2H), 2.67 (t, J=7.7 Hz,2H), 2.17-2.07 (m, 1H), 2.05 (s, 3H), 2.04-1.94 (m, 1H), 1.80-1.70 (m,2H), 1.69-1.60 (m, 2H), 1.60-1.46 (m, 2H), 1.38-1.17 (m, 14H), 0.89 (t,J=6.9 Hz, 3H); ¹³C NMR (101 MHz, Methanol-d₄) δ 180.61, 173.38, 169.55,148.11, 130.10, 128.33, 125.24, 47.76, 40.44, 36.84, 33.30, 33.06,32.44, 30.70, 30.56, 30.45, 30.30, 27.94, 23.74, 23.68, 22.37, 14.46;HRMS (ESI+): Calcd for C₂₅H₄₁N₄O₂ [M+H]⁺: 429.3224, Found: 429.3225.

4-(2-methyl-1,3-dioxolan-2-yl)benzonitrile (22)

4-acetylbenzonitrile (2.00 g, 12.78 mmol), ethylene glycol (7.68 mL,137.8 mmol), and ammonium chloride (0.37 g, 6.89 mmol) were added to around bottom flask containing toluene with Dean-Stark apparatusattached. The mixture was heated to reflux overnight (16-20 hours). Uponcooling to room temperature, excess potassium carbonate was added toquench acid, followed by filtration. Concentration in vacuo afforded thecrude product, which was then purified on silica gel (10% ethyl acetatein hexanes) to afford 22 (2.4393 g, 94%) as a white solid. ¹H NMR (400MHz, Chloroform-d) δ 7.60 (q, J=8.0 Hz, 4H), 4.14-3.95 (m, 2H),3.77-3.69 (m, 2H), 1.61 (s, 3H); ¹³C NMR (101 MHz, Chloroform-d) δ148.77, 132.25, 126.23, 118.82, 111.85, 108.22, 64.73, 27.45.

N′-hydroxy-4-(2-methyl-1,3-dioxolan-2-yl)benzimidamide (23)

To a round bottom flask containing ethanol was added4-(2-methyl-1,3-dioxolan-2-yl)benzonitrile (2.44 g, 12.90 mmol),hydroxylamine hydrochloride (1.79 g, 25.79 mmol), and triethylamine(8.99 mL, 64.48 mmol) under ambient air. The reaction mixture was thenheated to reflux for 4 hours. The resulting solution was allowed to coolto room temperature, followed by concentration in vacuo, to afford thecrude mixture as a solid. Purification on silica gel (60% ethyl acetatein hexanes) afforded 23 (2.59 g, 91%) as a white solid. ¹H NMR (400 MHz,Methanol-d₄) δ 7.62 (d, J=8.1 Hz, 2H), 7.49 (d, J=8.1 Hz, 2H), 4.88 (s,2H), 4.15-3.89 (m, 2H), 3.81-3.62 (m, 2H), 1.59 (s, 3H); ¹³C NMR (101MHz, Methanol-d₄) δ 155.14, 146.29, 133.71, 127.14, 126.42, 109.69,65.52, 27.82.

tert-butyl(3-(3-(4-(2-methyl-1,3-dioxolan-2-yl)phenyl)-1,2,4-oxadiazol-5-yl)propyl)carbamate(24)

N′-hydroxy-4-(2-methyl-1,3-dioxolan-2-yl)benzimidamide (0.50 g, 2.25mmol), 4-((tert-butoxycarbonyl)amino)butanoic acid (23) (0.50 g, 2.48mmol), and DIEA (2.40 mL, 13.50 mmol) were added to a round bottom flaskcontaining DMF at room temperature. HCTU (1.40 g, 3.38 mmol) was thenadded and the resulting mixture was heated to 100° C. for 4 hours. Uponcooling to room temperature, the reaction mixture was diluted in ethylacetate and washed with a saturated lithium bromide solution. Theresulting aqueous layer was then extracted with ethyl acetate. Theorganic layers were then combined and washed with a brine solution,followed by drying over anhydrous sodium sulfate. Concentration in vacuoafforded the crude product, which was then purified by silica gel (30%ethyl acetate/hexanes). Yellow oil (0.76 g, 86%). ¹H NMR (400 MHz,Chloroform-d) δ 7.99 (d, J=8.3 Hz, 2H), 7.55 (d, J=8.2 Hz, 2H), 4.97 (s,1H), 4.10-3.91 (m, 2H), 3.85-3.66 (m, 2H), 3.24 (q, J=6.5 Hz, 2H), 2.96(t, J=7.5 Hz, 2H), 2.03 (p, J=7.1 Hz, 2H), 1.62 (s, 3H), 1.39 (s, 9H);¹³C NMR (101 MHz, Chloroform-d) δ 179.40, 168.03, 156.03, 146.52,127.39, 126.38, 125.87, 108.59, 79.35, 64.56, 39.78, 28.42, 27.48,26.95, 24.10; HRMS (ESI+): Calcd for C₂₀H₂₈N₃O₅[M+H]⁺: 390.2023, Found:390.2023.

tert-butyl (3-(3-(4-acetylphenyl)-1,2,4-oxadiazol-5-yl)propyl)carbamate(25)

To a round bottom flask was added tert-butyl(3-(3-(4-(2-methyl-1,3-dioxolan-2-yl)phenyl)-1,2,4-oxadiazol-5-yl)propyl)carbamate(24) (0.75 g, 1.93 mmol), followed by a 1:1:1 solution ofAcOH:H₂O:acetone. The mixture was heated to 70° C. for 3 hours. Uponcooling to room temperature, the solution was washed with saturatedsodium bicarbonate and extracted with ethyl acetate. The organic layerswere then combined and washed with a brine solution, followed by dryingover anhydrous sodium sulfate. Concentration in vacuo afforded the crudeproduct, which was then purified by silica gel (30% ethylacetate/hexanes). White solid (0.42 g, 63%). ¹H NMR (400 MHz,Chloroform-d) δ 8.14 (d, J=8.3 Hz, 2H), 8.02 (d, J=8.4 Hz, 2H), 4.86 (t,J=6.2 Hz, 1H), 3.27 (q, J=6.5 Hz, 2H), 3.00 (t, J=7.5 Hz, 2H), 2.62 (s,3H), 2.07 (p, J=7.0 Hz, 2H), 1.41 (s, 9H); ¹³C NMR (101 MHz,Chloroform-d) δ 197.52, 179.89, 167.60, 156.06, 138.98, 131.03, 128.83,127.69, 79.51, 39.81, 28.47, 27.02, 26.85, 24.15; HRMS (ESI+): Calcd forC₁₈H₂₄N₃O₄ [M+H]⁺: 346.1761, Found: 346.1760.

tert-butyl(3-(3-(4-(1-(hydroxyimino)ethyl)phenyl)-1,2,4-oxadiazol-5-yl)propyl)carbamate(26)

tert-butyl (3-(3-(4-acetylphenyl)-1,2,4-oxadiazol-5-yl)propyl)carbamate(25) (0.42 g, 1.21 mmol), hydroxylamine hydrochloride (0.17 g, 2.41mmol), and sodium carbonate (0.26 g, 2.41 mmol) were added to a roundbottom flask, followed by a 1:1 solution of EtOH:H₂O. The mixture wasthen refluxed for 16 hours. Upon cooling to room temperature, themixture was filtered and concentrated in vacuo. The solution wasextracted with ethyl acetate. The organic layers were then combined andwashed with a brine solution, followed by drying over anhydrous sodiumsulfate. Concentration in vacuo afforded the crude product, which wasthen purified by silica gel (30% ethyl acetate/hexanes). White solid(0.31 g, 72%). ¹H NMR (400 MHz, Chloroform-d) δ 9.67 (s, 1H), 8.04 (d,J=8.1 Hz, 2H), 7.71 (d, J=8.2 Hz, 2H), 4.97 (s, 1H), 3.32-3.24 (m, 2H),2.98 (t, J=7.5 Hz, 2H), 2.30 (s, 3H), 2.15-1.98 (m, 2H), 1.43 (s, 9H);¹³C NMR (101 MHz, Chloroform-d) δ 179.60, 167.84, 156.19, 155.07,139.34, 127.57, 127.26, 126.45, 79.69, 39.82, 28.48, 26.94, 24.12,12.15; HRMS (ESI+): Calcd for C₁₈H₂₅N₄O₄ [M+H]⁺: 361.1870, Found:361.1870.

tert-butyl(3-(3-(4-(1-((4-phenylbutoxy)imino)ethyl)phenyl)-1,2,4-oxadiazol-5-yl)propyl)carbamate(27)

tert-butyl(3-(3-(4-(1-(hydroxyimino)ethyl)phenyl)-1,2,4-oxadiazol-5-yl)propyl)carbamate(26) (0.10 g, 0.28 mmol) was added to a round bottom flask containingEtOH. To this solution was added KOH (0.03 g, 0.55 mmol) and stirred for30 minutes at room temperature. (4-bromobutyl)benzene (0.18 g, 0.83mmol) was then added to the solution and the mixture was heated to 90°C. for 16 hours. Upon cooling to room temperature, the mixture wasfiltered and concentrated in vacuo. The solution was extracted withethyl acetate. The organic layers were then combined and washed with abrine solution, followed by drying over anhydrous sodium sulfate.Concentration in vacuo afforded the crude product, which was thenpurified by silica gel (20% ethyl acetate/hexanes). Yellow oil (0.06 g,46%). ¹H NMR (400 MHz, Chloroform-d) δ 8.06 (d, J=8.2 Hz, 2H), 7.76 (d,J=8.2 Hz, 2H), 7.33-7.24 (m, 2H), 7.23-7.14 (m, 3H), 4.90-4.77 (m, 1H),4.25 (t, J=6.0 Hz, 2H), 3.29 (q, J=6.6 Hz, 2H), 3.00 (t, J=7.5 Hz, 2H),2.69 (t, J=7.1 Hz, 2H), 2.25 (s, 3H), 2.08 (p, J=7.0 Hz, 2H), 1.83-1.78(m, 2H), 1.77-1.73 (m, 2H), 1.44 (s, 9H); ¹³C NMR (101 MHz,Chloroform-d) δ 179.49, 168.01, 156.05, 153.49, 142.47, 139.46, 128.51,128.38, 127.47, 127.12, 126.45, 125.82, 79.50, 74.33, 39.84, 35.75,28.95, 28.48, 27.92, 27.04, 24.16, 12.60; HRMS (ESI+): Calcd forC₂₈H₃₇N₄O₄ [M+H]⁺: 493.2809, Found: 493.2811.

1-(4-(5-(3-aminopropyl)-1,2,4-oxadiazol-3-yl)phenyl)ethan-1-one0-(4-phenylbutyl) oxime hydrochloride (28)

To a 6-dram vial containing tert-butyl(3-(3-(4-(1-((4-phenylbutoxy)imino)ethyl)phenyl)-1,2,4-oxadiazol-5-yl)propyl)carbamate(27) (0.06 g, 0.12 mmol) was added hydrogen chloride (0.3 mL, 1.22 mmol,4M in dioxane). The resulting mixture was allowed to stir at roomtemperature for 16 hours. The resulting solution was concentrated invacuo, washed 3 times with diethyl ether, and then purified by silicagel (0-20% methanol/dichloromethane). White solid (0.03 g, 55%). ¹H NMR(400 MHz, Methanol-d₄) δ 8.03 (d, J=8.5 Hz, 2H), 7.79 (d, J=8.5 Hz, 2H),7.27-7.20 (m, 2H), 7.20-7.07 (m, 3H), 4.38-3.92 (m, 2H), 3.08 (t, J=7.5Hz, 2H), 2.95 (t, J=7.4 Hz, 2H), 2.70-2.59 (m, 2H), 2.23 (s, 3H), 2.13(p, J=7.5 Hz, 2H), 1.79-1.74 (m, 2H), 1.74-1.69 (m, 2H); ¹³C NMR (101MHz, Methanol-d₄) δ 181.05, 169.08, 154.65, 143.62, 140.76, 129.42,129.29, 128.34, 128.26, 127.54, 126.73, 75.16, 40.83, 36.59, 29.89,29.07, 28.00, 24.55, 12.44; HRMS (ESI+): Calcd for C₂₃H₂₉N₄O₂ [M+H]⁺:393.2285, Found: 393.2275.

SP Transporter Assay

Transporter assays are vectorial and therefore require measurement ofthe transported analyte in different compartments. The S1P transporterSPNS2 only exports S1P, which obviates measuring uptake of S1P intotransporter-expressing cells. Thus, transporter activity was determinedby quantifying S1P release from whole cells expressing SPNS2. SPNS2inhibitor potency was assessed using whole cell assays. HeLa or U937cells expressing mouse SPNS2 were used to determine inhibitor potency(IC₅₀). Cells were plated onto 12 well plates and assayed when the cellmonolayers became confluent. Cell growth media (RPMI-1640 containing 10%fetal bovine serum) was replaced with 2 mL of serum-free media(RPMI-1640) containing fatty acid free bovine serum albumin (BSA) (0.2%w/v) and supplemented with 4-deoxypyridoxine (DOP) (1 mM), NaF (2 mM),Na₃VO₄ (0.2 mM) to inhibit S1P degradation. Test articles (1×10-9-1×10-4M) were assayed in duplicate or triplicate. After 18 hours, media wascollected, an internal recovery standard (0.005 mL of 5×10-7 Mdeuterated (d7) S1P in methanol) was added, the BSA was precipitatedwith trichloroacetic acid and the bound S1P extracted with methanol. S1Pand S1P-d7 were measured by liquid chromatography mass spectrometry.Inhibitor potency at the human SPNS2 ortholog was determined by ananalogous assay using U-937 cells, which endogenously express humanSPNS2.

TABLE 2 In vitro inhibition data against SPNS2 for exemplary compoundsof the disclosure (A ≤2 μM, B >2 μM). Compound Structure IC₅₀ 5a

B 5b

A 5c

B 5d

B 5e

A 5f

A 5g

B 5h

A 5i

B 5j

A 5k

B 5l

B 5m

B 5n

B 5n

B 5p

B 5q

B 5r

B 5s

B 5t

B 5u

B 5v

A 5w

A 5x

B 5y

B 6a

B 6b

B 6c

B 6d

B 6e

B 6f

B 7a

B 7b

B 9a

A 9b

B 9c

B 9d

A 9e

B 9f

B 9g

A 9h

A 9i

A 9j

A 9k

A 9l

A 9m

A 9n

B 9o

B 9p

B 9q

B 9r

A 9s

B 9t

B 9u

A 9v

B 9w

B 9x

B 9y

B 9z

A  9aa

A  9ab

B  9ac

B  9ad

B  9ae

B  9af

B  9ag

A  9ah

A  9ai

A  9aj

B  9ak

A  9al

B 13a 

B 13b 

B 13c 

B 13d 

B 16a 

A 16b 

B 19a 

A 19b 

B 19c 

A 19d 

B 21 

B 28 

B

1. A compound according to Formula I:

wherein X is a C₆-C₁₀-aryl or 5- to 10-membered heteroaryl (wherein 1 to4 heteroaryl ring members are independently selected from N, O, and S);R¹ and R² are independently selected from the group consisting of H,C₁-C₆-alkyl, C₁-C₆-alkoxy, C₁₋₆₋haloalkoxy, C₃-C₈-cycloalkyl,C₁-C₆-haloalkyl, CN, halo, and —C(O)N(H)(C₁-C₆-alkyl); W is a bond, O,NH, —NHC(O)—, or —O—(N═)C(R)— (wherein R is H or C₁-C₆-alkyl); V isselected from the group consisting of H, C₁-C₁₄-alkyl, C₂-C₁₂-alkenyl,(C₆-C₁₀)aryl, (C₆-C₁₀)heteroaryl, —C₁-C₁₀-alkyl-(C₆-C₁₀)aryl,—C₂-C₁₂-alkenyl-(C₆-C₁₀)aryl, —C₁-C₁₀-alkyl-(C₃-C₈)cycloalkyl, -(3- to14-membered heterocycloalkyl) (wherein 1-4 heterocycloalkyl members areindependently selected from N, O, and S), —(C₁-C₁₀)alkyl-(3- to14-membered heterocycloalkyl) (wherein 1-4 heterocycloalkyl members areindependently selected from N, O, and S); Y is selected from a bond,—NH—, (C₆-C₁₀)arylenyl, and (C₃-C₈)cycloalkylenyl; Z is selected from abond and —C(O)—; R³ and R⁴ are independently selected from the groupconsisting of, H, C₁-C₆-alkyl, OH, C₁-C₆₋alkoxy, halo, —NRR′, —C(O)R,and —C(O)OR, wherein R and R′ are independently selected from H andC₁-C₆-alkyl; R⁵ and R⁶ are independently selected from the groupconsisting of, H, C₁-C₆-alkyl, OH, C₁-C₆₋alkoxy, halo, —C(O)R, and—C(O)OR, wherein R is H or C₁-C₆-alkyl; or R⁵ and R⁶, together with thecarbon to which they are bound, form a —(C₃-C₈)cycloalkyl; m is aninteger selected from 0, 1, 2, 3, 4, 5, and 6; n is an integer selectedfrom 0, 1, and 2; R⁷ and R⁸ are independently selected from the groupconsisting of H and C₁-C₆-alkyl; or R⁷ and R⁸, together with thenitrogen atom to which they are bound, form a 5- to 7-memberedheterocycloalkyl (wherein 1-4 other heterocycloalkyl members areoptionally independently selected from NH, 0, and S); or, optionally,one of R⁵ and R⁶ and one of R⁷ and R⁸, together with the carbon andnitrogen atoms to which they are bound, respectively, form a 4- to7-membered heterocycloalkyl (wherein 1-4 other heterocycloalkyl membersare optionally independently selected from NH, O, and S); wherein eachalkyl, alkoxy, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, andheteroaryl is optionally substituted with 1-5 substituents independentlyselected from the group consisting of hydroxy, halo, C₁-C₆₋haloalkoxy,C₁-C₆-haloalkyl, —NR″₂, —NHC(O)(OC₁-C₆-alkyl), —NO₂, —CN, oxo, —C(O)OH,—C(O)O(C₁-C₆-alkyl), —C₁-C₆-alkyl(C₁-C₆-alkoxy), —C(O)NH₂, C₁-C₆-alkyl,—C(O)C₁-C₆-alkyl, —OC₁-C₆-alkyl, —Si(C₁-C₆-alkyl)₃,—S(O)₀₋₂-(C₁-C₆-alkyl), C₆-C₁₀-aryl, —(C₁-C₆-alkyl)(C₆-C₁₀-aryl), 3- to14-membered heterocycloalkyl, and —(C₁-C₆-alkyl)-(3- to 14-memberedheterocycle) (wherein 1-4 heterocycle members are independently selectedfrom N, O, and S), and —O(C₆-C₁₄-aryl); and wherein each R″ isindependently selected from the group consisting of C₁-C₆-alkyl,C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₆-C₁₀-aryl, 3- to 14-memberedheterocycloalkyl and —(C₁-C₆-alkyl)-(3- to 14-membered heterocycloalkyl)(wherein 1-4 ring members are independently selected from N, O, and S),and 5- to 10-membered heteroaryl (wherein 1-4 heteroaryl members areindependently selected from N, O, and S; or a pharmaceuticallyacceptable salt thereof.
 2. The compound or pharmaceutically acceptablesalt thereof according to claim 1, wherein, optionally, one of R⁵ and R⁶and one of R⁷ and R⁸, together with the carbon and nitrogen atoms towhich they are bound, respectively, form a 5- to 7-memberedheterocycloalkyl (wherein 1-4 other heterocycloalkyl members areoptionally independently selected from NH, O, and S).
 3. The compound orpharmaceutically acceptable salt thereof according to claim 1, wherein Xis phenyl.
 4. The compound or pharmaceutically acceptable salt thereofaccording to claim 3, wherein each of R¹ and R² is H.
 5. The compound orpharmaceutically acceptable salt thereof according to claim 4, whereineach of Y and Z is a bond.
 6. The compound or pharmaceuticallyacceptable salt thereof according to claim 5, wherein m is selected from0, 1, 2, 3, and
 4. 7. The compound or pharmaceutically acceptable saltthereof according to claim 6, wherein m is 1, 2, or
 3. 8. The compoundor pharmaceutically acceptable salt thereof according to claim 7,wherein m is 3 and n is 1 or
 2. 9. The compound or pharmaceuticallyacceptable salt thereof according to claim 8, wherein R⁷ and R⁸ areindependently selected from the group consisting of H and C₁-C₆-alkyl.10. The compound or pharmaceutically acceptable salt thereof claim 9,wherein each of R⁷ and R⁸ is H.
 11. The compound or pharmaceuticallyacceptable salt thereof according to claim 1, wherein Y is(C₃-C₈)cycloalkylenyl and Z is a bond.
 12. The compound orpharmaceutically acceptable salt thereof according to claim 11, whereinm is 0 or
 1. 13. The compound or pharmaceutically acceptable saltthereof according to claim 12, wherein m is
 0. 14. The compound orpharmaceutically acceptable salt thereof according to claim 13, whereinn is
 0. 15. The compound or pharmaceutically acceptable salt thereofaccording claim 4, wherein Y is —NH—.
 16. The compound orpharmaceutically acceptable salt thereof according to claim 15, whereinZ is —C(O)—.
 17. The compound or pharmaceutically acceptable saltthereof according to claim 16, wherein m is 0 or
 1. 18. The compound orpharmaceutically acceptable salt thereof according to claim 17, whereinone of R⁵ and R⁶ and one of R⁷ and R⁸, together with the carbon andnitrogen atoms to which they are bound, respectively, form a 5- to7-membered heterocycloalkyl.
 19. The compound or pharmaceuticallyacceptable salt thereof according to claim 18, wherein the other one ofR⁷ and R⁸ is H.
 20. The compound or pharmaceutically acceptable saltthereof according to claim 1, wherein X is phenyl; W is a bond and V isC₁-C₁₄-alkyl; R¹ and R² are independently selected from H andC₁-C₆₋alkyl; each of Y and Z is a bond; m is 3, 4, or 5 and n is 0; andR⁷ and R⁸ are independently selected from H and C₁-C₆₋alkyl.
 21. Thecompound or pharmaceutically acceptable salt thereof according to claim1, wherein the compound is selected from the following table: CompoundStructure 5a

5b

5c

5d

5e

5f

5g

5h

5i

5g

5k

5l

5m

5n

5n

5p

5q

5r

5s

5t

5u

5v

5w

5x

5y

6a

6b

6c

6d

6e

6f

7a

7b

9a

9b

9c

9d

9e

9f

9g

9h

9i

9j

9k

9l

9m

9n

9o

9p

9q

9r

9s

9t

9u

9v

9w

9x

9y

9z

 9aa

 9ab

 9ac

 9ad

 9ae

 9af

 9ag

 9ah

 9ai

 9aj

 9ak

 9al

13a 

13b 

13c 

13d 

16a 

16b 

19a 

19b 

19c 

19d 

21 

28 


22. A pharmaceutical composition comprising a compound orpharmaceutically acceptable salt thereof or a pharmaceuticallyacceptable salt thereof according to claim
 1. 23. A method of inhibitingspinster homolog 2 (SPNS2), comprising contacting SPNS2 with aneffective amount of a compound or pharmaceutically acceptable saltthereof according to claim
 1. 24. The method according to claim 23,wherein the contacting occurs in vivo.
 25. A method of treating apatient afflicted by a neoplastic disease, an allergic disease, or anautoimmune disease, comprising administering to the patient atherapeutically effective amount of a compound or pharmaceuticallyacceptable salt thereof claim
 1. 26. The method according to claim 25,wherein the neoplastic disease is metastatic neoplasms; the allergicdisease is asthma; and the autoimmune disease is multiple sclerosis orcomprises one or more progressive forms of multiple sclerosis, type Idiabetes, inflammatory bowel diseases, Crohn's disease, ulcerativecolitis, Grave's disease, Addison's disease, dermatomyositis, myastheniagravis, systemic lupus erythematosus, scleroderma, or psoriasis. 27.-32.(canceled)